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WO2024003331A1 - Spirolactone comme nouvelle tête de série antimicrobienne - Google Patents

Spirolactone comme nouvelle tête de série antimicrobienne Download PDF

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WO2024003331A1
WO2024003331A1 PCT/EP2023/067953 EP2023067953W WO2024003331A1 WO 2024003331 A1 WO2024003331 A1 WO 2024003331A1 EP 2023067953 W EP2023067953 W EP 2023067953W WO 2024003331 A1 WO2024003331 A1 WO 2024003331A1
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compound
botrytis
spores
staphylococcus
seq
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WO2024003331A9 (fr
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Ling Ding
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Danmarks Tekniske Universitet
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Danmarks Tekniske Universitet
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Priority to AU2023301447A priority Critical patent/AU2023301447A1/en
Priority to EP23736344.5A priority patent/EP4547243A1/fr
Priority to CA3259968A priority patent/CA3259968A1/fr
Publication of WO2024003331A1 publication Critical patent/WO2024003331A1/fr
Publication of WO2024003331A9 publication Critical patent/WO2024003331A9/fr
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/365—Lactones
    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
    • A01N43/00—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds
    • A01N43/90—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having two or more relevant hetero rings, condensed among themselves or with a common carbocyclic ring system
    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01P—BIOCIDAL, PEST REPELLANT, PEST ATTRACTANT OR PLANT GROWTH REGULATORY ACTIVITY OF CHEMICAL COMPOUNDS OR PREPARATIONS
    • A01P1/00—Disinfectants; Antimicrobial compounds or mixtures thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/10—Antimycotics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P33/00—Antiparasitic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D493/00—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system
    • C07D493/12—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system in which the condensed system contains three hetero rings
    • C07D493/20—Spiro-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N1/00—Microorganisms, e.g. protozoa; Compositions thereof; Processes of propagating, maintaining or preserving microorganisms or compositions thereof; Processes of preparing or isolating a composition containing a microorganism; Culture media therefor
    • C12N1/14—Fungi; Culture media therefor
    • C12N1/145—Fungal isolates
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12P—FERMENTATION OR ENZYME-USING PROCESSES TO SYNTHESISE A DESIRED CHEMICAL COMPOUND OR COMPOSITION OR TO SEPARATE OPTICAL ISOMERS FROM A RACEMIC MIXTURE
    • C12P17/00—Preparation of heterocyclic carbon compounds with only O, N, S, Se or Te as ring hetero atoms
    • C12P17/02—Oxygen as only ring hetero atoms
    • C12P17/04—Oxygen as only ring hetero atoms containing a five-membered hetero ring, e.g. griseofulvin, vitamin C
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12P—FERMENTATION OR ENZYME-USING PROCESSES TO SYNTHESISE A DESIRED CHEMICAL COMPOUND OR COMPOSITION OR TO SEPARATE OPTICAL ISOMERS FROM A RACEMIC MIXTURE
    • C12P17/00—Preparation of heterocyclic carbon compounds with only O, N, S, Se or Te as ring hetero atoms
    • C12P17/16—Preparation of heterocyclic carbon compounds with only O, N, S, Se or Te as ring hetero atoms containing two or more hetero rings
    • C12P17/162—Heterorings having oxygen atoms as the only ring heteroatoms, e.g. Lasalocid
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12P—FERMENTATION OR ENZYME-USING PROCESSES TO SYNTHESISE A DESIRED CHEMICAL COMPOUND OR COMPOSITION OR TO SEPARATE OPTICAL ISOMERS FROM A RACEMIC MIXTURE
    • C12P7/00—Preparation of oxygen-containing organic compounds
    • C12P7/24—Preparation of oxygen-containing organic compounds containing a carbonyl group
    • C12P7/26—Ketones
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12R—INDEXING SCHEME ASSOCIATED WITH SUBCLASSES C12C - C12Q, RELATING TO MICROORGANISMS
    • C12R2001/00—Microorganisms ; Processes using microorganisms
    • C12R2001/645—Fungi ; Processes using fungi

Definitions

  • the present invention relates, generally, to beta-lactones comprising a spiral-fused ring and a beta-lactone ring, and derivatives thereof, and their use as antimicrobial agents.
  • Obafluorin ( Figure 1.1), an antibiotic produced by Peudomonas fluorescens, exhibits antibacterial activity against Staphylococcus aureus, Escherichia coli, Enterobacter cloacae, Providencia rettgeri and Pseudomonas aeruginosa.
  • Salinosporamide ( Figure 1.2), isolated from the marine bacterium Salinospora tropica, is a cytotoxic proteasome inhibitor and completed phase 2 clinical trial for multiple myeloma cancer therapy.
  • Lipstatin ( Figure 1.3), isolated from Streptomyces toxytricini, is a potent and selective inhibitor of human pancreatic lipase, and it is currently used in clinic as anti-obese drug.
  • Actinomycetes are producers of small bioactive molecules exhibiting a broad range of structural and functional diversity called secondary metabolites (SMs). These compounds are relevant to human health, as many display pharmaceutical properties such as antibacterial, antifungal, anticancer and immunosuppressive activities. Nearly two thirds of antibiotics approved for clinical use originate from actinomycete bacteria, and of all new drugs from 1981-201460 % of the 1211 approved small molecule drugs were SMs or derivatives thereof.
  • the fungal infections it is used to treat include mucormycosis, aspergillosis, blastomycosis, candidiasis, coccidioidomycosis, and cryptococcosis.
  • Amphotericin B is considered a first-line treatment for severe fungal infections when other antifungal agents are ineffective or contraindicated, however, amphotericin B is also well known for its severe and potentially lethal side effects. Very often, it causes a serious reaction soon after infusion (within 1 to 3 hours), consisting of high fever, shaking chills, hypotension, anorexia, nausea, vomiting, headache, dyspnea and tachypnea, drowsiness, and generalized weakness.
  • the present disclosure concerns a compound comprising: a spiro-fused ring; and a beta-lactone ring, or a derivative thereof, such as an acceptable derivative thereof, for use in the prophylaxis and/or treatment of an infection or a condition, wherein said infection or condition is caused by a microorganism, and wherein the compound has formula (I): wherein: i. R4 is independently selected from the group consisting of: hydrogen, alkyl and halogen; P6215PC00 ii. R 1 , R 2 and R 3 is selected from the group consisting of: hydrogen; oxo; hydroxy; and methoxy; iii.
  • R 5 is selected from the group consisting of hydrogen; alkyl; halogen; oxo; hydroxy; methoxy; and formula (IV):
  • the present disclosure concerns the use of the compound as described herein as a disinfectant, as an antifungal agent, as an antibiotic, or as a bactericidal agent.
  • the present disclosure concerns a method of disinfecting a surface comprising a microorganism such as a pathogenic microorganism, said method comprising contacting a compound as defined herein.
  • the present disclosure concerns an isolated nucleic acid comprising or consisting of a nucleic acid selected from the group consisting of: i) splA as set forth in SEQ ID NO: 1; ii) splB as set forth in SEQ ID NO: 2; iii) splC as set forth in SEQ ID NO: 3; iv) splD as set forth in SEQ ID NO: 4; v) splE as set forth in SEQ ID NO: 5; vi) splF as set forth in SEQ ID NO: 6; vii) splG as set forth in SEQ ID NO: 7; viii) splH as set forth in SEQ ID NO: 8; ix) splI as set forth in SEQ ID NO: 9; x) splJ as set forth in SEQ ID NO: 10; xi) splK as set forth in SEQ ID NO: 11; and xii)
  • the present disclosure concerns the use of a cell as defined herein for producing the compound as defined herein, preferably wherein the cell is a Streptomyces cell such as a Streptomyces iranensis cell.
  • the present disclosure concerns a cell, such as a non-natural cell, expressing one or more heterologous proteins selected from the group consisting of: i) splA as set forth in SEQ ID NO: 13; ii) splB as set forth in SEQ ID NO: 14; iii) splC as set forth in SEQ ID NO: 15; iv) splD as set forth in SEQ ID NO: 16; v) splE as set forth in SEQ ID NO: 17; vi) splF as set forth in SEQ ID NO: 18; vii) splG as set forth in SEQ ID NO: 19; viii) splH as set forth in SEQ ID NO: 20; ix
  • the present disclosure concerns a vector or a system of vectors comprising any one of the isolated nucleic acids selected from the group consisting of: i) splA as set forth in SEQ ID NO: 1; ii) splB as set forth in SEQ ID NO: 2; iii) splC as set forth in SEQ ID NO: 3; iv) splD as set forth in SEQ ID NO: 4; v) splE as set forth in SEQ ID NO: 5; vi) splF as set forth in SEQ ID NO: 6; P6215PC00 vii) splG as set forth in SEQ ID NO: 7; viii) splH as set forth in SEQ ID NO: 8; ix) splI as set forth in SEQ ID NO: 9; x) splJ as set forth in SEQ ID NO: 10; xi) sp
  • the present disclosure concerns a method for the prophylaxis and/or treatment of an infection or a condition, wherein the method comprises administering a compound comprising: a spiro-fused ring; and a beta-lactone ring, or a derivative thereof, such as an acceptable derivative thereof, wherein said infection or condition is caused by a microorganism and wherein the compound has formula (I): wherein: i. R4 is independently selected from the group consisting of: hydrogen, alkyl and halogen; P6215PC00 ii. R 1 , R 2 and R 3 is selected from the group consisting of: hydrogen; oxo; hydroxy; and methoxy; iii.
  • R 5 is selected from the group consisting of hydrogen; alkyl; halogen; oxo; hydroxy; methoxy; and formula (IV): (IV).
  • the present disclosure concerns the use of a compound comprising: a spiro-fused ring; and a beta-lactone ring, or a derivative thereof, such as an acceptable derivative thereof, for the prophylaxis and/or treatment of an infection or a condition in an agricultural product, wherein said infection or condition is caused by a microorganism, and wherein the compound has formula (I): wherein: i. R 4 is independently selected from the group consisting of: hydrogen, alkyl and halogen; P6215PC00 ii.
  • R 1 , R 2 and R 3 is selected from the group consisting of: hydrogen; oxo; hydroxy; and methoxy; iii.
  • R 5 is selected from the group consisting of hydrogen; alkyl; halogen; oxo; hydroxy; methoxy; and formula (IV): (IV).
  • the present disclosure concerns the use of a cell capable of producing the compound as described herein in a method for preventing growth of a microorganism on a surface or a plant, preferably wherein the cell is a Streptomyces cell such as a Streptomyces iranensis cell, wherein the cell is as defined herein.
  • the present disclosure concerns a method of treating or preventing an infection or a condition caused by a microorganism, said method comprising administering or applying to a subject in need thereof the compound as described herein.
  • Figure 1 discloses examples of previous reported beta-lactones.1: Obafluorin, 2: Salinosporamide, 3: Lipostatin.
  • Figure 2 shows selected HMBC correlations for spirolactone.
  • Figure 3 discloses the ORTEP diagram showing the atom-numbering scheme and solid-state conformation of spirolactone.
  • Figure 4 discloses the proposed biosynthesis of spirolactone.
  • Figure 5 discloses the Biosynthetic Gene Cluster and individual genes for spirolactone.
  • Figure 6 discloses the CRISPR-cas9 mutation on SplA abolished the production of spirolactone.
  • Figure 7 discloses agar diffusion assay showing strong inhibition for spirolactone (10 ⁇ g/paper disk) against three Aspergillus species. The inhibition zones are 50 mm, 40 mm and 70 mm, respectively.
  • Figure 8 discloses agar diffusion assay showing strong inhibition for spirolactone (50 ⁇ g/paper disk) against Gram-positive human pathogen S. aureus strain 8325. The inhibition zone is 19 mm.
  • alkyl refers to a straight or branched hydrocarbon chain radical consisting of carbon and hydrogen atoms, containing no unsaturation, and may be straight or branched, substituted or unsubstituted.
  • the alkyl group may consist of 1 to 12 carbon atoms, e.g.1 carbon atom, 2 carbon atoms, 3 carbon atoms, 4 carbon atoms etc., up to and including 12 carbon atoms.
  • Exemplary alkyl groups include, but are in no way limited to, methyl, ethyl, propyl, isopropyl, n- butyl, iso-butyl, sec-butyl isobutyl, tertiary butyl, pentyl, isopentyl, neopentyl, hexyl, septyl, octyl, nonyl and decyl.
  • the alkyl moiety may be attached to the rest of the molecule by a single bond, such as for example, methyl (Me), ethyl (Et), n-propyl (Pr), 1-methylethyl (iso-propyl), n-butyl, n-pentyl, 1,1-dimethylethyl (t-butyl) and 3- methylhexyl.
  • an alkyl group is optionally substituted by one or more of any suitable substituents.
  • An alkyl group can be mono-, di-, tri- or tetra-valent, as appropriate to satisfy valence requirements.
  • alkylene by itself or as part of another substituent, means a divalent radical derived from an alkyl moiety, as exemplified, but not limited, by ⁇ CH2CH2CH2CH2 ⁇ .
  • suitable substituents for substituted groups disclosed herein independently include, but are not limited to, alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, hydroxy, halo, cyano, trifluoromethyl, trifluoromethoxy, nitro, trimethylsilanyl, chloride, bromide, ⁇ OR a , ⁇ SR a , ⁇ OC(O) ⁇ R a , ⁇ N(R a ) 2 , ⁇ C(O)R a , ⁇ C(O)OR a , ⁇ OC(O)N(R a ) 2 , ⁇ OR a
  • nucleic acid refers to polynucleotides such as deoxyribonucleic acid (DNA) and ribonucleic acid (RNA) or a combination of the two and any chemical or enzymatic modification thereof (e.g. methylated DNA, DNA of modified nucleotides).
  • DNA deoxyribonucleic acid
  • RNA ribonucleic acid
  • isolated nucleic acid refers to a nucleic acid that is separated from its native environment and present in sufficient quantity to permit its identification or use.
  • An isolated nucleic acid may be one that is (i) amplified in vitro by, for example, polymerase chain reaction (PCR); (ii) recombinantly produced or cloned; (iii) purified, as by cleavage and gel separation; or (iv) synthesized by, for example, chemical synthesis.
  • An isolated nucleic acid is one which is readily manipulable by recombinant DNA techniques well known in the art.
  • PCR polymerase chain reaction
  • nucleic acid may be substantially purified, but need not be.
  • a nucleic acid that is isolated within a cloning or expression vector is not pure in that it may comprise a small percentage of the material of the cell in which it resides.
  • Such a nucleic acid is isolated, however, as the term is used herein because it is readily manipulable by standard techniques known to those of ordinary skill in the art. Any of the nucleic acids provided herein may be isolated.
  • the term “gene” as used herein means a nucleic acid sequence that contains information necessary for expression of a polypeptide or protein. It includes the promoter and terminator and the structural gene as well as other sequences involved in expression of the protein.
  • protein or “polypeptide” as defined herein are used interchangeably and refer to molecules consisting of a chain of amino acids, without reference to a specific mode of action, size, 3-dimensional structure or origin. A fragment or portion of a protein may thus still be referred to as a "protein".
  • An "isolated protein” is used to refer to a protein which is no longer in its natural environment, for example in vitro.
  • a “heterologous protein” refers to a protein which is not naturally present in the cell in which it is expressed, for example it is expressed in a recombinant bacterial or plant host cell.
  • An enzyme is a protein having enzymatic activity.
  • vector means a DNA molecule capable of replication in a host cell and/or to which another DNA segment can be operatively linked so as to bring about replication of the attached segment.
  • a plasmid is an exemplary vector.
  • a system of vectors comprising several nucleic acids comprises a plurality of vectors, which together comprise a plurality of nucleic acids.
  • the nucleic acids are not necessarily all on the same vector; a vector of the system of vectors may comprise several nucleic acids.
  • a system of vectors comprising five nucleic acids can be: a first vector comprising a first and a second nucleic acids, and a second vector comprising a third, a fourth and a fifth nucleic acids; or five vectors each comprising one of the first, second, third, fourth and fifth nucleic acids.
  • the term “host cell” as defined herein refers to a cell which includes an exogenous polynucleotide, wherein the methods used to insert the exogenous polynucleotide into a cell include direct uptake, transduction, f-mating, or other methods known in the art to create recombinant host cells.
  • exogenous polynucleotide may be a non-integrated vector, including but not limited to a plasmid, or may be integrated into the host genome.
  • non-natural microorganism refers to a microorganism that has been manipulated to include an exogenous polynucleotide.
  • exogenous polynucleotide may be a non-integrated vector, including but not limited to a plasmid, or may be integrated into the host genome.
  • a non-natural microorganism may thus express a heterologous protein, i.e. a protein which is not naturally found in the microorganism.
  • P6215PC00 The terms homology, identity and similarity, with respect to a polynucleotide (or polypeptide), as defined herein are used interchangeably and refer to the percentage of nucleic acids (or amino acids) in the candidate sequence that are homolog, identical or similar, respectively, to the residues of a corresponding native nucleic acids (or amino acids), after aligning the sequences and introducing gaps, if necessary, to achieve the maximum percent homology/identity / similarity, and considering any conservative substitutions according to the NCIUB rules (hftp://www.chem.qmul.ac.uk/iubmb/misc/naseq.html; NC-IUB, Eur J Biochem (1985)) as part of the sequence identity.
  • the percentage of similarity refers to the percentage of residues conserved with similar physiochemical properties. Neither 5' or 3' extensions nor insertions (for nucleic acids) or N’ or C’ extensions nor insertions (for polypeptides) result in a reduction of identity or similarity. Methods and computer programs for the alignments are well known in the art. Generally, a given similarity between two sequences implies that the identity between these sequences is at least equal to the similarity; for example, if two sequences are 70% identical to one another, they cannot be less than 70% similar to one another – but could be sharing 80% similarity or more.
  • the term “at least 70% homology, similarity or identity” means at least 75%, at least 80%, at least 85%, at least 90%, at least 95% homology, similarity or identity throughout the present disclosure.
  • the term “functional variant” refers herein to functional variants of a parent polypeptide, such as an enzyme, which retain at least some of the activity of the parent polypeptide, such as the parent enzyme.
  • a functional variant of a Type I PKS can catalyse the same conversion as the enzymes from which they are derived, although the efficiency of reaction may be different, e.g. the efficiency is decreased or increased compared to the parent enzyme, the substrate specificity is modified, the longevity or turnover of the enzyme is modified, the cellular localisation of the enzyme is modified.
  • a variant of a nucleic acid is a variant of a given nucleic acid, preferably DNA, sequence, which given sequence encodes a given polypeptide.
  • a variant in this context refers to a nucleic acid which differs from the given nucleic acid, but still encodes a functional polypeptide. In other words, the term variant encompasses all sequences encoding the same polypeptide as the given nucleic acid sequence.
  • the variant encodes a polypeptide, the sequence of which differs from the sequence of the given polypeptide, but retains all or at least part of the functionality of the given polypeptide.
  • a variant may thus encode a polypeptide which has lower (but not null) functionality as the given polypeptide, or similar functionality as the given polypeptide, or higher functionality as the given polypeptide. How to test whether the functionality of the polypeptide obtained from the variant is modified compared to the given polypeptide is well within reach of the skilled person. It can for example be assessed by purifying the resulting polypeptide, e.g. using an affinity tag, and assaying its activity on a given substrate in vitro.
  • spiro-fused ring as defined herein is meant to include two molecular rings with only one common atom.
  • microorganism as defined herein is meant to include a bacterium, yeast and/or fungus.
  • antibiotic-resistant bacteria as defined herein is meant to include bacteria that are resistant to antibiotics routinely used in the clinics.
  • mg/kg refers to a concentration of a certain amount of mg of the compound as defined herein per one kg of a recipient, wherein the recipient can be an animal, an agricultural product, and/or the soil.
  • agricultural products as defined herein is meant to include agricultural, horticultural, viticultural, and dairy products, livestock and the products thereof, the products of poultry and bee raising, the edible products of forestry, and any and all products raised or produced on farms and processed or manufactured products thereof, transported or intended to be transported in interstate and/or foreign commerce.
  • a compound comprising: a spiro-fused ring; and a beta-lactone ring, wherein the compound has formula (I): wherein: i. R4 is independently selected from the group consisting of: hydrogen, alkyl and halogen; ii. R1, R2 and R3 is selected from the group consisting of: hydrogen; oxo; hydroxy; and methoxy; iii.
  • R5 is selected from the group consisting of hydrogen; alkyl; halogen; oxo; hydroxy; methoxy; and formula (IV): P6215PC00 (IV)” encompasses a compound of formula (III): throughout the present disclosure.
  • the term “spirolactone” encompasses a compound of formula (III):
  • P6215PC00 throughout the present disclosure.
  • compounds comprising a spiro-fused ring, and a beta-lactone ring, in particular spirolactone (a compound of formula (III)) are useful as antimicrobial agent, as a disinfectant, as an antifungal agent, as an antibiotic, or as a bactericidal agent.
  • said compounds can be also useful to disinfect a surface.
  • the present disclosure further describes the genes and the gene cluster encoding the proteins involved in synthesis of compounds comprising a spiro-fused ring, and a beta- lactone ring, in particular spirolactone (a compound of formula (III)).
  • the compounds of the present disclosure describes a compound comprising a spiro-fused ring; and a beta-lactone ring, or a derivative thereof, in particular spirolactone, which is suitable for the use and methods described herein, in particular methods to prevent or treat infections cause by microorganisms in animals and/or plants and methods to disinfect a surface.
  • the compound of the present disclosure has formula (I): P6215PC00 or is a derivative thereof, such as an acceptable derivative thereof, such as a salt or solvate thereof, such as an acceptable salt or an acceptable solvate thereof; wherein, R4 is independently selected from the group consisting of: hydrogen, alkyl and halogen; R1, R2 and R3 is selected from the group consisting of: hydrogen; oxo; hydroxy; and methoxy; R 5 is selected from the group consisting of hydrogen; alkyl; halogen; oxo; hydroxy; methoxy; and formula (IV): In some embodiments, the compound of the present disclosure has formula (II): P6215PC00 or is a derivative thereof, such as an acceptable derivative thereof, such as a salt or solvate thereof, such as an acceptable salt or an acceptable solvate thereof.
  • R1 is hydroxy. In some embodiments of the present disclosure, R2 is hydroxy. In some embodiments of the present disclosure, R3 is methoxy. In some embodiments of the present disclosure, R4 is hydroxy. In some embodiments of the present disclosure, R4 is a C1-6 alkyl. In some embodiments of the present disclosure, R4 is methyl. In some embodiments of the present disclosure, R5 is hydroxy. In some embodiments of the present disclosure, R5 is a C1-8 alkyl. In some embodiments of the present disclosure, R5 is halogen. In some embodiments of the present disclosure, R5 is oxo. In some embodiments of the present disclosure, R5 is hydroxy.
  • R 5 is methoxy. In some embodiments of the present disclosure, R 5 has formula (IV): P6215PC00 In some embodiments of the present disclosure, R1 is - hydroxy, R2 is hydroxy, R3 is methoxy, R4 is hydroxyl, R5 has formula (IV): P6215PC00 Effective concentration of the compounds
  • said compounds of formula (I) comprising a spiro-fused ring, and a beta-lactone ring, in particular spirolactone, are useful as antimicrobial agent, as a disinfectant, as an antifungal agent, as an antibiotic, or as a bactericidal agent.
  • said compounds can be also useful to disinfect a surface.
  • Such compounds in particular spirolactone (a compound of formula (III)), can be used as an alternative to other antimicrobial agents, such as amphotericin B.
  • the present disclosure describes that said compounds have comparable or lower minimal inhibition concentration than amphotericin B toward some fungi.
  • compounds of formula (I) comprising a spiro- fused ring, and a beta-lactone ring, in particular spirolactone (a compound of formula (III)
  • the compounds of the present disclosure are useful in the prophylaxis and/or treatment of an infection or a condition, wherein said infection or condition is caused by a microorganism, in particular an antibiotic-resistant Gram-positive bacteria.
  • the compound of the present disclosure is administered between 0.05 and 1 mg of the compound/kg of a recipient, between 0.05 and 2 mg/kg, between 0.05 and 3 mg/kg, between 0.05 and 4 mg/kg, between 0.05 and 5 mg/kg, between 0.05 and 6 mg/kg, between 0.05 and 7 mg/kg, between 0.05 and 8 mg/kg, between 0.05 and 9 mg/kg, between 0.05 and 10 mg/kg, between 0.06 and 1 mg/kg, between 0.06 and 2 mg/kg, between 0.06 and 3 mg/kg, between 0.06 and 4 mg/kg, between 0.06 and 5 mg/kg, between 0.06 and 6 mg/kg, between 0.06 and 7 mg/kg, between 0.06 and 8 mg/kg, between 0.06 and 9 mg/kg, between 0.06 and 10 mg/kg,
  • the compound of the present disclosure is administered between 0.5 and 1 mg of the compund/kg of a recipient, wherein the recipient is an animal, an agricultural product, and/or the soil.
  • the minimal inhibition concentration of the compound against the microorganism causing the condition is lower than 100 ⁇ g/mL, lower than 90 ⁇ g/mL, lower than 80 ⁇ g/mL, lower than 70 ⁇ g/mL, lower than 60 ⁇ g/mL, lower than 50 ⁇ g/mL, lower than 40 ⁇ g/mL, lower than 30 ⁇ g/mL, lower than 20 ⁇ g/mL, lower than 15 ⁇ g/mL, lower than 10 ⁇ g/mL, lower than 5 ⁇ g/mL, lower than 3 ⁇ g/mL, lower than 1 ⁇ g/mL.
  • the minimal inhibition concentration of the compound against the microorganism causing the condition is at least 2-fold, at P6215PC00 least 3-fold, at least 5-fold, at least 10-fold, at least 20-fold, at least 30-fold, at least 40- fold, at least 50-fold, at least 60-fold, at least 70-fold, at least 80-fold, at least 90-fold, at least 100-fold, at least 110-fold, at least 120-fold, at least 130-fold, at least 140-fold, at least 150-fold, at least 160-fold, at least 170-fold, at least 180-fold, at least 190-fold, at least 200-fold lower than the minimal inhibition concentration of Amphoterin B towards a microorganism of the same species, preferably towards the same microorganism.
  • the compound is a compound of formula (I) as described herein comprising a spiro-fused ring and a beta-lactone ring or a derivative thereof.
  • the compound is the compound of formula (II), preferably the compound of formula (III).
  • Microorganisms susceptible to the compounds of the present disclosure are useful as antimicrobial agents.
  • said compounds are useful in the prophylaxis and/or treatment of an infection or a condition, wherein said infection or condition is caused by a microorganism, preferably wherein said microorganism is selected from the group consisting of: a Gram-positive bacterium and a fungus.
  • the microorganism is a pathogenic microorganism.
  • the microorganism is a fungus.
  • the fungus belongs to the division Ascomycota.
  • the fungus belongs to the class Eurotiomycetes, Dothideomycetes, and/or Leotiomycetes.
  • the fungus belongs to the class Eurotiomycetes and/or Dothideomycetes.
  • the fungus belongs to the class Eurotiomycetes and/or Leotiomycetes.
  • the fungus belongs to the class Dothideomycetes, and/or Leotiomycetes. In some embodiments of the present disclosure, the fungus belongs to the class Eurotiomycetes. In some embodiments of the present disclosure, the fungus belongs to the class Dothideomycetes. In some embodiments of the present disclosure, the fungus belongs to the class Leotiomycetes. In some embodiments of the present disclosure, the fungus belongs to the order Eurotiales, Pleosporales, and/or Helotiales. In some embodiments of the present disclosure, the fungus belongs to the order Eurotiales and/or Pleosporales.
  • the fungus belongs to the order Eurotiales and/or Helotiales. In some embodiments of the present disclosure, fungus belongs to the order Pleosporales and/or Helotiales. In some embodiments of the present disclosure, the fungus belongs to the order Eurotiales. In some embodiments of the present disclosure, fungus belongs to the order Pleosporales. In some embodiments of the present disclosure, fungus belongs to the order Helotiales. In some embodiments of the present disclosure, the fungus belongs to the family Trichocomaceae, Pleosporaceae, and/or Sclerotiniaceae.
  • the fungus belongs to the family Trichocomaceae and/or Pleosporaceae. In some embodiments of the present disclosure, the fungus belongs to the family Trichocomaceae and/or Sclerotiniaceae. In some embodiments of the present disclosure, the fungus belongs to the family Pleosporaceae, and/or Sclerotiniaceae. In some embodiments of the present disclosure, the fungus belongs to the family Trichocomaceae. In some embodiments of the present disclosure, the fungus belongs to the family Pleosporaceae. In some embodiments of the present disclosure, the fungus belongs to the family Sclerotiniaceae.
  • the fungus belongs to the genus Aspergillus, Alternaria, and/or Botrytis. In some embodiments of the present disclosure, the fungus belongs to the genus Aspergillus and/or Alternaria. In some embodiments of the present disclosure, the fungus belongs to the genus Aspergillus and/or Botrytis. In some embodiments of the present disclosure, the fungus belongs to the genus Alternaria, and/or Botrytis. In some embodiments of the present disclosure, the fungus belongs to the genus Aspergillus. In some embodiments of the present disclosure, the fungus belongs to the genus Alternaria.
  • the fungus belongs to the genus Botrytis.
  • the Aspergillus is selected from the group consisting of: Aspergillus fumigatus; Aspergillus niger; Aspergillus flavus; Aspergillus nidulans; Aspergillus tubingensis, Aspergillus alliaceus; Aspergillus arachidicola; Aspergillus carbonarius; Aspergillus clavatus; Aspergillus felis; Aspergillus flavipes; Aspergillus japonicas; Aspergillus lentulus; Aspergillus minisclerotigens; Aspergillus mottae; Aspergillus nomius; Aspergillus parasiticus; Aspergillus ochraceus; Aspergillus terreus; Aspergillus transmontanensi; Aspergillus sergi
  • the Aspergillus belongs to Section Circumdati; Section Flavi; or Section Nigri.
  • the Aspergillus is selected from the group consisting of: Aspergillus fumigatus; Aspergillus niger; Aspergillus flavus; Aspergillus nidulans; and Aspergillus tubingensis.
  • the Alternaria is selected from the group consisting of: Alternaria solani; Alternaria alternate; Alternaria arborescens; Alternaria arbusti; Alternaria blumeae; Alternaria brassicae; Alternaria brassicicola; Alternaria burnsii; Alternaria carotiincultae; Alternaria carthami; Alternaria celosiae; Alternaria cinerariae; Alternaria citri; Alternaria conjuncta; Alternaria cucumerina; Alternaria dauci; Alternaria dianthi; Alternaria dianthicola; Alternaria eichhorniae; Alternaria euphorbiicola; Alternaria gaisen; Alternaria helianthi; Alternaria helianthicola; P6215PC00 Alternaria hungarica; Alternaria infectoria; Alternaria japonica; Alternaria limicola; Alternaria linicola; Alternaria long
  • the Alternaria is Alternaria solani.
  • the Botrytis is selected from the group consisting of: Botrytis cinerea; Botrytis aclada; Botrytis allii; Botrytis allii-fistulosi; Botrytis ampelophila; Botrytis anacardii; Botrytis anthophila; Botrytis argillacea; Botrytis arisaemae; Botrytis artocarpi; Botrytis bifurcate; Botrytis bryi; Botrytis capsularum; Botrytis carnea; Botrytis caroliniana; Botrytis carthami; Botrytis cercosporaecola; Botrytis cercosporicola; Botrytis citricola; Botrytis citrina; Botrytis convallariae; Botrytis croci; Botrytis cryptom
  • the Botrytis is Botrytis cinerea.
  • the microorganism is a bacterium , preferably a Gram-positive bacterium.
  • the Gram-positive bacterium belongs to the genus selected from the group consisting of: Staphylococcus; Clostridium; and Streptococcus. P6215PC00 In some embodiments of the present disclosure, the Gram-positive bacterium belongs to the genus Staphylococcus.
  • the Staphylococcus is selected from the group consisting of: Staphylococcus aureus; Staphylococcus argenteus; Staphylococcus aureus; Staphylococcus schweitzeri; Staphylococcus simiae; Staphylococcus auricularis; Staphylococcus carnosus; Staphylococcus condiment; Staphylococcus debuckii; Staphylococcus massiliensis; Staphylococcus piscifermentans; Staphylococcus simulans; Staphylococcus capitis; Staphylococcus caprae; Staphylococcus epidermidis; Staphylococcus saccharolyticus; Staphylococcus borealis; Staphylococcus devriesei; Staphylococcus haemolyticus; Staphylococcus hominis; Staphylococcus agnetis;
  • the Staphylococcus is selected from the group consisting of: Staphylococcus aureus; Staphylococcus argenteus; Staphylococcus aureus; Staphylococcus schweitzeri; and Staphylococcus simiae.
  • the Staphylococcus is Staphylococcus aureus.
  • the infection or condition caused by the microorganism is aspergillosis. P6215PC00
  • the compound of formula (I) as described herein comprising a spiro-fused ring and a beta-lactone ring or a derivative thereof can be used against such infections.
  • the compound is the compound of formula (II), preferably the compound of formula (III).
  • Animals and agricultural products affected by the infection or the condition The compounds of formula (I) as described herein of the present disclosure, in particular spirolactone, are useful for the prophylaxis and/or treatment of an infection or a condition caused by microorganisms that are capable of infecting animals and/or plants.
  • the infection or the condition caused by the microorganism affects an animal or an agricultural product.
  • the infection or the condition caused by the microorganism affects an animal.
  • the compound is administered to an animal or applied to an agricultural product.
  • the compound is administered to an animal.
  • the animal is a mammal.
  • the animal is selected from the group consisting of: a human; a cat; a dog; a cow, a pig; a horse; a sheep; a goat; a llama; a mouse; a rat; a monkey; a porpoise; a fish; an insect, such as a bee; a reptile; and/or a marine invertebrate.
  • the animal is a human.
  • the condition caused by the microorganism affects an agricultural product.
  • the compound is applied to an agricultural product.
  • the agricultural product is a plant or a product derived from a plant.
  • P6215PC00 The plant contacted by any one of said compounds comprising a spiro-fused ring, and a beta-lactone ring, in particular compounds of formula (II) or (III) such as spirolactone, can belong to any variety of plant.
  • the present compounds and methods can be applied to any variety of plant.
  • the agricultural product is selected from the group consisting of: almond; anemone; apple; apricot; asparagus; avocado; azalea; banana; beet; bell pepper; blueberry; broccoli; cabbage; caneberries; canola; carrot; cereal; coffee; cherries; chickpea; cole crops; cocoa; corn; cotton; cucumber; date palm; Dianthus; Dracena; eggplant; figs; ginseng; garlic; gourd; grape; grapefruit; grapevine; horseradish; hot pepper; leek; legumes; lemon; lentil; lettuce; lime; mango; melon; nut; oil seed rape; onion; orange; palm oil; papaya; parsley; parsnip; pea; peach; peanut; pear; pineapple; pistachio; pomelo; potato; pumpkin; raisins; sesame seeds; squash; soybean; spice; strawberry; sunflower; sweet potato; tea; tobacco; tomato; tree nut; verbena; walnut; watermelon; wheat; y
  • the infection or a condition is caused by a fungus, such as a fungus that belongs to the division Ascomycota, such as a fungus that belongs to the class Eurotiomycetes, Dothideomycetes, and/or Leotiomycetes, such as a fungus that belongs to the order Eurotiales, Pleosporales, or Helotiales, such as a fungus that belongs to the family Trichocomaceae, Pleosporaceae, and/or Sclerotiniaceae, such as a fungus belongs to the genus Aspergillus, Alternaria, and/or Botrytis.
  • a fungus such as a fungus that belongs to the division Ascomycota, such as a fungus that belongs to the class Eurotiomycetes, Dothideomycetes, and/or Leotiomycetes, such as a fungus that belongs to the order Eurotiales, Pleo
  • the infection or a condition is caused by a fungus that belongs to the genus Aspergillus, preferably Aspergillus fumigatus; Aspergillus niger; Aspergillus flavus; Aspergillus nidulans; and Aspergillus tubingensis, and the animal is a human; a cat; a dog; a cow, a pig; a horse; a sheep; a goat; a llama; a mouse; a rat; a monkey; a porpoise; a fish; an insect, such as a bee; a reptile; and/or a marine invertebrate.
  • a fungus that belongs to the genus Aspergillus, preferably Aspergillus fumigatus; Aspergillus niger; Aspergillus flavus; Aspergillus nidulans; and Aspergillus tubingensis
  • the animal
  • the infection or a condition is caused by a fungus that belongs to the genus Aspergillus, preferably Aspergillus fumigatus; Aspergillus niger; Aspergillus flavus; Aspergillus nidulans; and Aspergillus tubingensis, and the agricultural product is selected from the group consisting of: apricot; cereal; cocoa; coffee; corn; cotton; date P6215PC00 palm; grape; maize; onions; palm oil; papaya; peanuts; pineapple; pistachio; sesame seeds; spices; strawberry; tomato; tree nut; and walnut.
  • the agricultural product is selected from the group consisting of: apricot; cereal; cocoa; coffee; corn; cotton; date P6215PC00 palm; grape; maize; onions; palm oil; papaya; peanuts; pineapple; pistachio; sesame seeds; spices; strawberry; tomato; tree nut; and walnut.
  • the infection or a condition is caused by a fungus that belongs to the genus Alternaria, prefereably Alternaria solani, and the agricultural product is selected from the group consisting of: bell pepper; eggplant; hot pepper; potato; and tomato.
  • the infection or a condition is caused by a fungus that belongs to the genus Botrytis, preferably Botrytis cinerea
  • the agricultural product is selected from the group consisting of: almond; anemone; apple; apricot; asparagus; avocado; beet; caneberries; canola; carrot; cherries; chickpea; grape; legumes; lentil; lettuce; mango; maize; pea; peach; peanut; pear; pistachio; potato; strawberry; sunflower; sweet potato; tea; tobacco; tomato; and verbena.
  • the infection or a condition is caused by a Gram-positive bacterium, such as a Staphylococcus; Clostridium; and Streptococcus, preferably a Staphylococcus aureus
  • the infected subject is an animal, such as a human; such as a cat; such as a dog; such as a cow, such as a pig; such as a horse; such as a sheep; such as a goat; such as a llama; such as a mouse; such as a rat; a monkey; such as a porpoise; such as a fish; such as an insect, such as a bee; such as a reptile; and/or such as a marine invertebrate.
  • a Gram-positive bacterium such as a Staphylococcus; Clostridium; and Streptococcus, preferably a Staphylococcus aureus
  • the infected subject is an animal, such as a human;
  • the compound is a compound of formula (I) as described herein comprising a spiro-fused ring and a beta-lactone ring or a derivative thereof and can be administered to an animal or an agricultural product.
  • the compound is the compound of formula (II), preferably the compound of formula (III).
  • the compound is a compound of formula (I) comprising a spiro- fused ring and a beta-lactone ring or a derivative thereof and can be used in the prophylaxis and/or treatment of an infection or a condition caused by a microorganism, wherein the infection or a condition affects an animal or an agricultural product.
  • the compound is the compound of formula (II), preferably the compound of formula (III).
  • P6215PC00 Supplementing microorganism producing the compound The present compounds can be provided to or contacted with a plant as described herein using any method known by a person skilled in the art, such as irrigation, or such as seed-coating, or such as foliar spray.
  • said compounds of formula (I) as described herein comprising a spiro-fused ring, and a beta-lactone ring, is spirolactone, a compound of formula (III). Said compounds might be supplemented to the soil as one compound or as any combination of multiple compounds.
  • Said compounds disclosed above can be supplied to the soil in which the plant is grown as a pure compound, as a lysate of said cell producing the compound, by supplementation of said cells producing the compound, as part of said cultivation broth comprising the compound and/or cells producing the compound, as detailed herein.
  • the compound is supplied via supplementation of microorganisms producing the compound.
  • the microorganism producing the compound belongs to the genus Streptomyces.
  • the Streptomyces is Streptomyces iranensis.
  • the microorganism producing the compound is supplied as a liquid spore solution and/or as dried solid spores at a concentration between 0.01 and 2x10 4 cfu/cm 2 , between 0.01 and 5x10 4 cfu/cm 2 , between 0.01 and 10x10 4 cfu/cm 2 , between 0.01 and 50x10 4 cfu/cm 2 , between 0.01 and 100x10 4 cfu/cm 2 , between 0.01 and 200x10 4 cfu/cm 2 , between 0.01 and 500x10 4 cfu/cm 2 , between 0.01 and 1000x10 4 cfu/cm 2 , between 0.1 and 2x10 4 cfu/cm 2 , between 0.1 and 5x10 4 cfu/cm 2 , between 0.1 and 10x10 4 cfu/cm 2 , between 0.1 and 50x10 4 cfu/cm 2
  • the microorganism producing the compound is supplied as a liquid spore solution at a concentration between 0.001 and 2x10 9 spores/mL, between 0.001 and 5x10 9 spores/mL, between 0.001 and 10x10 9 spores/mL, between 0.001 and 20x10 9 spores/mL, between 0.001 and 30x10 9 spores/mL, between 0.001 and 40x10 9 spores/mL, between 0.001 and 50x10 9 spores/mL, between 0.001 and 60x10 9 spores/mL, between 0.001 and 70x10 9 spores/mL, between 0.001 and 80x10 9 spores/mL, between 0.001 and 90x10 9 spores/mL, between 0.001 and 100x10 9 spores/mL, between 0.015 and 2x10 9 spores/mL, between 0.0
  • the microorganism producing the compound is supplied as a liquid spore solution at a concentration between 0.1 and 10 x10 9 spores/mL, preferably 1.5x10 9 spores/mL.
  • the liquid spore solution is supplied to the leaves of a plant.
  • the microorganism producing the compound is supplied as dried solid spores at a concentration between 0.1 and 150x10 9 spores/mL, between 0.1 and 200x10 9 spores/mL, between 0.1 and 10x10 9 spores/mL, between 0.1 and 20x10 9 spores/mL, between 0.1 and 30x10 9 spores/mL, between 0.1 and 40x10 9 spores/mL, between 0.1 and 50x10 9 spores/mL, between 0.1 and 60x10 9 spores/mL, between 0.1 and 70x10 9 spores/mL, between 0.1 and 80x10 9 spores/mL, between 0.1 and 90x10 9 spores/mL, between 0.1 and 100x10 9 spores/mL, between 1 and 150x10 9 spores/mL, between 1 and 200x10 9 spores/mL, between 1 and
  • the microorganism producing the compound is supplied as dried solid spores at a concentration between 50 and 200X10 9 spores/mL, preferably 100X10 9 spores/mL. In some embodiments of the present disclosure, dried solid spores are supplemented into the soil.
  • Compositions and formulations The compounds described herein, are useful as antimicrobial agent, as disinfectant, as antifungal agent, as antibiotic, or as bactericidal agent. Furthermore, said compounds can be also useful to disinfect a surface.
  • the compound of the present disclosure is formulated as a gel, as a spray, or as a wipe. This can be done by methods which are well known to the skilled person.
  • the compound of the present disclosure is comprised within a composition.
  • the composition further comprises an acceptable carrier; for pharmaceutical applications, the carrier is preferably a pharmaceutically acceptable carrier.
  • the compounds of the present disclosure can be further combined with other disinfectants, antifungal agents, antibiotics, and/or bactericidal agent. Said combinations might aim to synergistically target a microorganism, and/or to target a wider list of microorganisms.
  • the composition further comprises at least one other disinfectant, such as an antibacterial agent having activity against Gram-negative bacteria, or such as an additional antibacterial agent having activity against Gram-positive bacteria.
  • the composition further comprises at least one other antifungal agent. In some embodiments of the present disclosure, the composition further comprises at least one other antibiotic. In some embodiments of the present disclosure, the composition further comprises at least one other bactericidal agent.
  • the composition comprising the compound can further comprise additional agents useful to disinfect surfaces, or compounds that make the application of the compound more pleasant, such as fragrances. Thus, in some embodiments of the present disclosure, the composition further comprises at least one degreasing agent, a fragrance, or both.
  • the composition is useful in in the prophylaxis and/or treatment of an infection or a condition, wherein said infection or condition is caused by a microorganism, wherein the microorganism is a pathogenic microorganism, such as a fungus, such as a fungus belonging to the division Ascomycota, such as a fungus belonging to the order Eurotiales or Pleosporales, such as a fungus belonging to the family Trichocomaceae or Pleosporaceae, such as a fungus belonging to the to the genus Aspergillus or Alternaria.
  • the subject to treat is an animal as defined herein, such as a mammal, preferably a human.
  • the microorganism is administered to the soil, and/or to an agricultural product as defined herein.
  • the microorganism causing the disease or condition affects an agricultural product as defined herein, such as almond; anemone; apple; apricot; asparagus; avocado; azalea; banana; beet; bell pepper; blueberry; broccoli; cabbage; caneberries; canola; carrot; cereal; coffee; cherries; chickpea; cole crops; cocoa; corn; cotton; cucumber; date palm; Dianthus; P6215PC00 Dracena; eggplant; figs; ginseng; garlic; gourd; grape; grapefruit; grapevine; horseradish; hot pepper; leek; legumes; lemon; lentil; lettuce; lime; mango; melon; nut; oil seed rape; onion; orange; palm oil; papaya; parsley; parsnip; pea; peach; peanut; pear; pineapple; pistachio; pomelo; potato; pumpkin; raisins; sesame seeds
  • the compound of formula (I) as described herein comprised in the composition comprises a spiro-fused ring and a beta-lactone ring or a derivative thereof.
  • the compound is the compound of formula (II), preferably the compound of formula (III).
  • Isolated nucleic acid discloses that the genes involved in synthesis of compounds of formula (I) as described herein comprising a spiro-fused ring and a beta-lactone ring or a derivative thereof, , such as the compound is the compound of formula (II), preferably the compound of formula (III), are: i) splA as set forth in SEQ ID NO: 1; ii) splB as set forth in SEQ ID NO: 2; iii) splC as set forth in SEQ ID NO: 3; iv) splD as set forth in SEQ ID NO: 4; v) splE as set forth in SEQ ID NO: 5; vi) splF as set forth in SEQ ID NO: 6; vii) splG as set forth in SEQ ID NO: 7; viii) splH as set forth in SEQ ID NO: 8; ix) splI as set forth in SEQ ID NO:
  • any of the above nucleic acids, or respective variants thereof having at least 70% homology, similarity or identity thereto, such as at least 80%, such as at least 90%, such as at least 91%, such as at least 92%, such as at least 93%, such as at least 94%, such as at least 95%, such as at least 96%, such P6215PC00 as at least 97%, such as at least 98%, such as at least 99%, such as 100% homology, similarity or identity thereto, can be introduced in a cell, whereby the cell can generate compounds of formula (I) as described herein comprising a spiro-fused ring and a beta- lactone ring or a derivative thereof.
  • compounds are compounds of formula (II) or a salt or derivative thereof, preferably the compound of formula (III).
  • Whole genome sequencing and bioinformatics analysis revealed that there are 44 biosynthetic gene clusters in Streptomyces iranensis HM 35 (NCBI taxonomy ID, 576784; sample ID, DSM41954).
  • Biosynthetic genes that are required to synthesize of compounds of formula (I) as described herein comprising a spiro-fused ring and a beta-lactone ring or a derivative thereof, in particular compounds of formula (II) or a salt or derivative thereof preferably the compound of formula (III), may comprise or consist of anyone of the genes in table 1. Table 1.
  • MJ126-NF4 S plI 654 42/54 WP_089101481.1 Streptomyces hyaluromycini S plJ 338 60/75 WP_106196453.1, Umezawaea tangerina SplK 394 58/72 MBR7672783.1, Streptomycesdaliensis S plL 403 53/68 WP_227725975.1, Streptomyces sp.
  • Vector or system of vectors comprising one or more of the isolated nucleic acids selected from the group consisting of: i) splA as set forth in SEQ ID NO: 1; ii) splB as set forth in SEQ ID NO: 2; iii) splC as set forth in SEQ ID NO: 3; iv) splD as set forth in SEQ ID NO: 4; v) splE as set forth in SEQ ID NO: 5; vi) splF as set forth in SEQ ID NO: 6; vii) splG as set forth in SEQ ID NO: 7; viii) splH as set forth in SEQ ID NO: 8; ix) splI as set forth in SEQ ID NO: 9; x) splJ as set forth in SEQ ID NO: 10; xi) splK as set forth
  • said vector or system of vectors comprises any combination of two or more isolated nucleic acids selected from the group consisting of: i) splA as set forth in SEQ ID NO: 1; ii) splB as set forth in SEQ ID NO: 2; iii) splC as set forth in SEQ ID NO: 3; iv) splD as set forth in SEQ ID NO: 4; v) splE as set forth in SEQ ID NO: 5; vi) splF as set forth in SEQ ID NO: 6; vii) splG as set forth in SEQ ID NO: 7; viii) splH as set forth in SEQ ID NO: 8; ix) splI as set forth in SEQ ID NO: 9; x) splJ as set forth in SEQ ID NO: 10; xi) splK as set forth in SEQ ID NO: 11; and P6215PC00 xi
  • said vector or system of vectors comprises two or more isolated nucleic acids selected from the group consisting of: i) splA as set forth in SEQ ID NO: 1; ii) splB as set forth in SEQ ID NO: 2; iii) splC as set forth in SEQ ID NO: 3; iv) splD as set forth in SEQ ID NO: 4; v) splE as set forth in SEQ ID NO: 5; vi) splF as set forth in SEQ ID NO: 6; vii) splG as set forth in SEQ ID NO: 7; viii) splH as set forth in SEQ ID NO: 8; ix) splI as set forth in SEQ ID NO: 9; x) splJ as set forth in SEQ ID NO: 10; xi) splK as set forth in SEQ ID NO: 11; and xii) splL as
  • said vector or system of vectors comprises all the isolated nucleic acids: i) splA as set forth in SEQ ID NO: 1; ii) splB as set forth in SEQ ID NO: 2; iii) splC as set forth in SEQ ID NO: 3; iv) splD as set forth in SEQ ID NO: 4; v) splE as set forth in SEQ ID NO: 5; vi) splF as set forth in SEQ ID NO: 6; vii) splG as set forth in SEQ ID NO: 7; viii) splH as set forth in SEQ ID NO: 8; P6215PC00 ix) splI as set forth in SEQ ID NO: 9; x) splJ as set forth in SEQ ID NO: 10; xi) splK as set forth in SEQ ID NO: 11; and xii) splL as set forth in
  • said vector or system of vectors comprises splA as set forth in SEQ ID NO: 1, and respective variants thereof having at least 70% homology, similarity or identity thereto.
  • said vector or system of vectors comprises splB as set forth in SEQ ID NO: 2, and respective variants thereof having at least 70% homology, similarity or identity thereto.
  • said vector or system of vectors comprises splC as set forth in SEQ ID NO: 3, and respective variants thereof having at least 70% homology, similarity or identity thereto.
  • said vector or system of vectors comprises splD as set forth in SEQ ID NO: 4, and respective variants thereof having at least 70% homology, similarity or identity thereto.
  • said vector or system of vectors comprises splE as set forth in SEQ ID NO: 5, and respective variants thereof having at least 70% homology, similarity or identity thereto.
  • said vector or system of vectors comprises splF as set forth in SEQ ID NO: 6, and respective variants thereof having at least 70% homology, similarity or identity thereto.
  • said vector or system of vectors comprises splG as set forth in SEQ ID NO: 7, and respective variants thereof having at least 70% homology, similarity or identity thereto.
  • said vector or system of vectors comprises splH as set forth in SEQ ID NO: 8, and respective variants thereof having at least 70% homology, similarity or identity thereto.
  • said vector or system of vectors comprises splI as set forth in SEQ ID NO: 9, and respective variants thereof having at least 70% homology, similarity or identity thereto.
  • said vector or system of vectors comprises splJ as set forth in SEQ ID NO: 10, and respective variants thereof having at least 70% homology, similarity or identity thereto.
  • said vector or system of vectors comprises splK as set forth in SEQ ID NO: 11, and respective variants thereof having at least 70% homology, similarity or identity thereto.
  • said vector or system of vectors comprises splL as set forth in SEQ ID NO: 12, and respective variants thereof having at least 70% homology, similarity or identity thereto.
  • said vector or system of vectors comprises two of the above listed isolated nucleic acids, or variants thereof having at least 70% homology, similarity or identity thereto, such as at least 80%, such as at least 90%, such as at least 91%, such as at least 92%, such as at least 93%, such as at least 94%, such as at least 95%, such as at least 96%, such as at least 97%, such as at least 98%, such as at least 99%, such as 100% homology, similarity or identity thereto.
  • the vector or system of vectors may comprise: i) splA and splB; ii) splA and splC; iii) splA and splD; P6215PC00 iv) splA and splE; v) splA and splF; vi) splA and splG; vii) splA and splH; viii) splA and splI; ix) splA and splJ; x) splA and splK; xi) splA and splL; or variants thereof having at least 70% homology, similarity or identity thereto, such as at least 80%, such as at least 90%, such as at least 91%, such as at least 92%, such as at least 93%, such as at least 94%, such as at least 95%, such
  • said vector or system of vectors comprises three of the above listed isolated nucleic acids, or respective variants thereof having at least 70% homology, similarity or identity thereto, such as at least 80%, such as at least 90%, such as at least 91%, such as at least 92%, such as at least 93%, such as at least 94%, such as at least 95%, such as at least 96%, such as at least 97%, such as at least 98%, such as at least 99%, such as 100% homology, similarity or identity thereto.
  • the vector or system of vectors may comprise: i) splA, splB, splC; ii) splA, splC, and splD; iii) splA, splE, and splF; iv) splA, splG, and splH; v) splA, splI, and splJ; vi) splA, splK, and splL; vii) splA, splB, and splD; viii) splA, splC, and splF; ix) splA, splE, and splH; x) splA, splG, and splJ; xi) splA, splI, and spl
  • said vector or system of vectors comprises four of the above listed isolated nucleic acids, or respective variants thereof having at least 70% homology, similarity or identity thereto, such as at least 80%, such as at least 90%, such as at least 91%, such as at least 92%, such as at least 93%, such as at least 94%, such as at least 95%, such as at least 96%, such as at least 97%, such as at least 98%, such as at least 99%, such as 100% homology, similarity or identity thereto.
  • the vector or system of vectors may comprise: i) splA, splB, splC, and splD; ii) splA, splC, splD, and splE; iii) splA, splE, splF, and splG; iv) splA, splG, splH, and splI; v) splA, splI, splJ, and splK; vi) splA, splB, splK, and splL; vii) splA, splB, splD, and splF; viii) splA, splC, splF, and splE; ix) splA, splE, and
  • said vector or system of vectors comprises five of the above listed isolated nucleic acids, P6215PC00 or respective variants thereof having at least 70% homology, similarity or identity thereto, such as at least 80%, such as at least 90%, such as at least 91%, such as at least 92%, such as at least 93%, such as at least 94%, such as at least 95%, such as at least 96%, such as at least 97%, such as at least 98%, such as at least 99%, such as 100% homology, similarity or identity thereto.
  • the vector or system of vectors may comprise: i) splA, splB, splC, splD, and splE; ii) splA, splC, splD, splE, and splG; iii) splA, splE, splF, splG, and splI; iv) splA, splG, splH, splI, and splK; v) splA, splI, splJ, splK, and splL; vi) splA, splB, splC, splK, and splL; vi) splA, splB, splC, splK, and splL; vii)
  • said vector or system of vectors comprises six of the above listed isolated nucleic acids, or respective variants thereof having at least 70% homology, similarity or identity thereto, such as at least 80%, such as at least 90%, such as at least 91%, such as at least 92%, such as at least 93%, such as at least 94%, such as at least 95%, such as at least 96%, such as at least 97%, such as at least 98%, such as at least 99%, such as 100% homology, similarity or identity thereto.
  • the vector or system of vectors may comprise: i) splA, splB, splC, splD, splE and splF; ii) splA, splC, splD, splE, splF, and splG; iii) splA, splE, splF, splG, splH, and splI; P6215PC00 iv) splA, splG, splH, splI, splJ, and splK; v) splA, splB, splI, splJ, splK, and splL; vi) splA, splB, splC, splD, splK, and sp
  • said vector or system of vectors comprises seven of the above listed isolated nucleic acids, or respective variants thereof having at least 70% homology, similarity or identity thereto, such as at least 80%, such as at least 90%, such as at least 91%, such as at least 92%, such as at least 93%, such as at least 94%, such as at least 95%, such as at least 96%, such as at least 97%, such as at least 98%, such as at least 99%, such as 100% homology, similarity or identity thereto.
  • the vector or system of vectors may comprise: i) splA, splB, splC, splD, splE, splF and splG; ii) splA, splC, splD, splE, splF, splG, and splH; iii) splA, splE, splF, splG, splH, splI, and splJ; iv) splA, splG, splH, splI, splJ, splK, and splL; v) splA, splB, splC, splI, splJ, splK, and splL; vi) splA, sp
  • said vector or system of vectors comprises eight of the above listed isolated nucleic acids, or respective variants thereof having at least 70% homology, similarity or identity thereto, such as at least 80%, such as at least 90%, such as at least 91%, such as at least 92%, such as at least 93%, such as at least 94%, such as at least 95%, such as at least 96%, such as at least 97%, such as at least 98%, such as at least 99%, such as 100% homology, similarity or identity thereto.
  • the vector or system of vectors may comprise: i) splA, splB, splC, splD, splE, splF, splG, and splH; ii) splA, splC, splD, splE, splF, splG, splH, and splI; iii) splA, splE, splF, splG, splH, splI, splJ, and splK; iv) splA, splB, splG, splH, splI, splJ, splK, and splL; v) splA, splB, splC, splG, splG
  • said vector or system of vectors comprises nine of the above listed isolated nucleic acids, P6215PC00 or respective variants thereof having at least 70% homology, similarity or identity thereto, such as at least 80%, such as at least 90%, such as at least 91%, such as at least 92%, such as at least 93%, such as at least 94%, such as at least 95%, such as at least 96%, such as at least 97%, such as at least 98%, such as at least 99%, such as 100% homology, similarity or identity thereto.
  • the vector or system of vectors may comprise: i) splA, splB, splC, splD, splE, splF, splG, splH, and splI; ii) splA, splC, splD, splE, splF, splG, splH, splI, and splJ; iii) splA, splE, splF, splG, splH, splI, splJ, splK, and splL; iv) splB, splD, splE, splG, splH, splI, splJ, splK, and splL; v) splB
  • said vector or system of vectors comprises ten of the above listed isolated nucleic acids, or respective variants thereof having at least 70% homology, similarity or identity thereto, such as at least 80%, such as at least 90%, such as at least 91%, such as at least 92%, such as at least 93%, such as at least 94%, such as at least 95%, such as at least 96%, such as at least 97%, such as at least 98%, such as at least 99%, such as 100% homology, similarity or identity thereto.
  • the vector or system of vectors may comprise: i) splA, splB, splC, splD, splE, splF, splG, splH, splI, and splJ; ii) splA, splC, splD, splE, splF, splG, splH, splI, splJ, and splK; iii) splA, splB, splE, splF, splG, splH, splI, splJ, splK, and splL; iv) splB, splD, splE, splF, splG, splH, splI, and s
  • said vector or system of vectors comprises eleven of the above listed isolated nucleic acids, or respective variants thereof having at least 70% homology, similarity or identity thereto, such as at least 80%, such as at least 90%, such as at least 91%, such as at least 92%, such as at least 93%, such as at least 94%, such as at least 95%, such as at least 96%, such as at least 97%, such as at least 98%, such as at least 99%, such as 100% homology, similarity or identity thereto.
  • the vector or system of vectors may comprise: i) splA, splB, splC, splD, splE, splF, splG, splH, splI, splJ and splK; ii) splA, splC, splD, splE, splF, splG, splH, splI, splJ, splK, and splL; iii) splA, splB, splD, splE, splF, splG, splH, splI, splJ, splK, and splL; iv) splA, splB, splC, splE, spl
  • said vector or system of vectors comprises all the above listed isolated nucleic acids, or respective variants thereof having at least 70% homology, similarity or identity thereto, such as at least 80%, such as at least 90%, such as at least 91%, such as at least 92%, such as at least 93%, such as at least 94%, such as at least 95%, such as at least 96%, such as at least 97%, such as at least 98%, such as at least 99%, such as 100% homology, similarity or identity thereto.
  • said vector or system of vectors comprises any one of the biosynthetic genes that are required to synthesize compounds comprising a spiro-fused ring and a beta-lactone ring, and respective variants thereof having at least 70% homology, similarity or identity thereto. In some embodiments, said vector or system of vectors comprises any one of the biosynthetic genes that are sufficient, when introduced in a cell as described herein, to synthesize compounds comprising a spiro-fused ring and a beta-lactone, and respective variants thereof having at least 70% homology, similarity or identity thereto.
  • the compound is a compound of formula (I) as described herein comprising a spiro-fused ring and a beta-lactone ring or a derivative thereof.
  • the compound is the compound of formula (II), preferably the compound of formula (III).
  • Cell producing the compound The present disclosure describes a cell producing a compound of formula (I) as described herein comprising a spiro-fused ring and a beta-lactone ring or a derivative thereof.
  • the compound is the compound of formula (II), preferably the compound of formula (III).
  • the disclosure is directed to a cell, such as a non-natural cell, expressing one or more heterologous proteins selected from the group consisting of: i) splA as set forth in SEQ ID NO: 13; ii) splB as set forth in SEQ ID NO: 14; iii) splC as set forth in SEQ ID NO: 15; iv) splD as set forth in SEQ ID NO: 16; v) splE as set forth in SEQ ID NO: 17; vi) splF as set forth in SEQ ID NO: 18; vii) splG as set forth in SEQ ID NO: 19; P6215PC00 viii) splH as set forth in SEQ ID NO: 20; ix) splI as set forth in SEQ ID NO: 21; x) splJ as
  • the cell comprises any one of the nucleic acid sequences selected from the group consisting of: i) splA as set forth in SEQ ID NO: 1; ii) splB as set forth in SEQ ID NO: 2; iii) splC as set forth in SEQ ID NO: 3; iv) splD as set forth in SEQ ID NO: 4; v) splE as set forth in SEQ ID NO: 5; vi) splF as set forth in SEQ ID NO: 6; vii) splG as set forth in SEQ ID NO: 7; viii) splH as set forth in SEQ ID NO: 8; ix) splI as set forth in SEQ ID NO: 9; x) splJ as set forth in SEQ ID NO: 10; xi) splK as set forth in SEQ ID NO: 11; and xii) splL
  • said cell comprises any combination of two or more nucleic acid sequences selected from the group consisting of: i) splA as set forth in SEQ ID NO: 1; ii) splB as set forth in SEQ ID NO: 2; iii) splC as set forth in SEQ ID NO: 3; iv) splD as set forth in SEQ ID NO: 4; v) splE as set forth in SEQ ID NO: 5; P6215PC00 vi) splF as set forth in SEQ ID NO: 6; vii) splG as set forth in SEQ ID NO: 7; viii) splH as set forth in SEQ ID NO: 8; ix) splI as set forth in SEQ ID NO: 9; x) splJ as set forth in SEQ ID NO: 10; xi) splK as set forth in SEQ ID NO: 11; and xii) s
  • said cell comprises two or more nucleic acid sequences selected from the group consisting of: i) splA as set forth in SEQ ID NO: 1; ii) splB as set forth in SEQ ID NO: 2; iii) splC as set forth in SEQ ID NO: 3; iv) splD as set forth in SEQ ID NO: 4; v) splE as set forth in SEQ ID NO: 5; vi) splF as set forth in SEQ ID NO: 6; vii) splG as set forth in SEQ ID NO: 7; viii) splH as set forth in SEQ ID NO: 8; ix) splI as set forth in SEQ ID NO: 9; x) splJ as set forth in SEQ ID NO: 10; xi) splK as set forth in SEQ ID NO: 11; and xii) splL as set forth in SEQ ID NO:
  • said cell comprises all the nucleic acid sequences: i) splA as set forth in SEQ ID NO: 1; ii) splB as set forth in SEQ ID NO: 2; iii) splC as set forth in SEQ ID NO: 3; iv) splD as set forth in SEQ ID NO: 4; P6215PC00 v) splE as set forth in SEQ ID NO: 5; vi) splF as set forth in SEQ ID NO: 6; vii) splG as set forth in SEQ ID NO: 7; viii) splH as set forth in SEQ ID NO: 8; ix) splI as set forth in SEQ ID NO: 9; x) splJ as set forth in SEQ ID NO: 10; xi) splK as set forth in SEQ ID NO: 11; and xii) splL as set forth in SEQ ID NO:
  • said cell comprises splA as set forth in SEQ ID NO: 1, and respective variants thereof having at least 70% homology, similarity or identity thereto.
  • said cell comprises splB as set forth in SEQ ID NO: 2, and respective variants thereof having at least 70% homology, similarity or identity thereto.
  • said cell comprises splC as set forth in SEQ ID NO: 3, and respective variants thereof having at least 70% homology, similarity or identity thereto.
  • said cell comprises splD as set forth in SEQ ID NO: 4, and respective variants thereof having at least 70% homology, similarity or identity thereto.
  • said cell comprises splE as set forth in SEQ ID NO: 5, and respective variants thereof having at least 70% homology, similarity or identity thereto.
  • said cell comprises splF as set forth in SEQ ID NO: 6, and respective variants thereof having at least 70% homology, similarity or identity thereto.
  • said cell comprises splG as set forth in SEQ ID NO: 7, and respective variants thereof having at least 70% homology, similarity or identity thereto.
  • P6215PC00 In some embodiments, said cell comprises splH as set forth in SEQ ID NO: 8, and respective variants thereof having at least 70% homology, similarity or identity thereto.
  • said cell comprises splI as set forth in SEQ ID NO: 9, and respective variants thereof having at least 70% homology, similarity or identity thereto.
  • said cell comprises splJ as set forth in SEQ ID NO: 10, and respective variants thereof having at least 70% homology, similarity or identity thereto.
  • said cell comprises splK as set forth in SEQ ID NO: 11, and respective variants thereof having at least 70% homology, similarity or identity thereto.
  • said cell comprises splL as set forth in SEQ ID NO: 12, and respective variants thereof having at least 70% homology, similarity or identity thereto.
  • said cell comprises two of the above listed nucleic acid sequences, or variants thereof having at least 70% homology, similarity or identity thereto, such as at least 80%, such as at least 90%, such as at least 91%, such as at least 92%, such as at least 93%, such as at least 94%, such as at least 95%, such as at least 96%, such as at least 97%, such as at least 98%, such as at least 99%, such as 100% homology, similarity or identity thereto.
  • the vector or system of vectors may comprise: i) splA and splB; ii) splA and splC; iii) splA and splD; iv) splA and splE; v) splA and splF; vi) splA and splG; vii) splA and splH; viii) splA and splI; ix) splA and splJ; x) splA and splK; xi) splA and splL; P6215PC00 or variants thereof having at least 70% homology, similarity or identity thereto, such as at least 80%, such as at least 90%, such as at least 91%, such as at least 92%, such as at least 93%, such as at least 94%, such as at least 95%, such
  • said cell comprises three of the above listed nucleic acid sequences, or respective variants thereof having at least 70% homology, similarity or identity thereto, such as at least 80%, such as at least 90%, such as at least 91%, such as at least 92%, such as at least 93%, such as at least 94%, such as at least 95%, such as at least 96%, such as at least 97%, such as at least 98%, such as at least 99%, such as 100% homology, similarity or identity thereto.
  • the vector or system of vectors may comprise: i) splA, splB, splC; ii) splA, splC, and splD; iii) splA, splE, and splF; iv) splA, splG, and splH; v) splA, splI, and splJ; vi) splA, splK, and splL; vii) splA, splB, and splD; viii) splA, splC, and splF; ix) splA, splE, and splH; x) splA, splG, and splJ; xi) splA, splI, and spl
  • said cell comprises four of the above listed nucleic acid sequences, P6215PC00 or respective variants thereof having at least 70% homology, similarity or identity thereto, such as at least 80%, such as at least 90%, such as at least 91%, such as at least 92%, such as at least 93%, such as at least 94%, such as at least 95%, such as at least 96%, such as at least 97%, such as at least 98%, such as at least 99%, such as 100% homology, similarity or identity thereto.
  • the vector or system of vectors may comprise: i) splA, splB, splC, and splD; ii) splA, splC, splD, and splE; iii) splA, splE, splF, and splG; iv) splA, splG, splH, and splI; v) splA, splI, splJ, and splK; vi) splA, splB, splK, and splL; vii) splA, splB, splD, and splF; viii) splA, splC, splF, and splE; ix) splA, splE, and
  • said cell comprises five of the above listed nucleic acid sequences, or respective variants thereof having at least 70% homology, similarity or identity thereto, such as at least 80%, such as at least 90%, such as at least 91%, such as at least 92%, such as at least 93%, such as at least 94%, such as at least 95%, such as at least 96%, such as at least 97%, such as at least 98%, such as at least 99%, such as 100% homology, similarity or identity thereto.
  • the vector or system of vectors may comprise: i) splA, splB, splC, splD, and splE; ii) splA, splC, splD, splE, and splG; iii) splA, splE, splF, splG, and splI; P6215PC00 iv) splA, splG, splH, splI, and splK; v) splA, splI, splJ, splK, and splL; vi) splA, splB, splC, splK, and splL; vii) splA, splB, splC, splD, and spl
  • said cell comprises six of the above listed nucleic acid sequences, or respective variants thereof having at least 70% homology, similarity or identity thereto, such as at least 80%, such as at least 90%, such as at least 91%, such as at least 92%, such as at least 93%, such as at least 94%, such as at least 95%, such as at least 96%, such as at least 97%, such as at least 98%, such as at least 99%, such as 100% homology, similarity or identity thereto.
  • the vector or system of vectors may comprise: i) splA, splB, splC, splD, splE and splF; ii) splA, splC, splD, splE, splF, and splG; iii) splA, splE, splF, splG, splH, and splI; iv) splA, splG, splH, splI, splJ, and splK; v) splA, splB, splI, splJ, splK, and splL; vi) splA, splB, splC, splD, splK, and splL;
  • said cell comprises seven of the above listed nucleic acid sequences, or respective variants thereof having at least 70% homology, similarity or identity thereto, such as at least 80%, such as at least 90%, such as at least 91%, such as at least 92%, such as at least 93%, such as at least 94%, such as at least 95%, such as at least 96%, such as at least 97%, such as at least 98%, such as at least 99%, such as 100% homology, similarity or identity thereto.
  • the vector or system of vectors may comprise: i) splA, splB, splC, splD, splE, splF and splG; ii) splA, splC, splD, splE, splF, splG, and splH; iii) splA, splE, splF, splG, splH, splI, and splJ; iv) splA, splG, splH, splI, splJ, splK, and splL; v) splA, splB, splC, splI, splJ, splK, and splL; vi) splA, sp
  • said cell comprises eight of the above listed nucleic acid sequences, P6215PC00 or respective variants thereof having at least 70% homology, similarity or identity thereto, such as at least 80%, such as at least 90%, such as at least 91%, such as at least 92%, such as at least 93%, such as at least 94%, such as at least 95%, such as at least 96%, such as at least 97%, such as at least 98%, such as at least 99%, such as 100% homology, similarity or identity thereto.
  • the vector or system of vectors may comprise: i) splA, splB, splC, splD, splE, splF, splG, and splH; ii) splA, splC, splD, splE, splF, splG, splH, and splI; iii) splA, splE, splF, splG, splH, splI, splJ, and splK; iv) splA, splB, splG, splH, splI, splJ, splK, and splL; v) splA, splB, splC, splG, splG
  • said cell comprises nine of the above listed nucleic acid sequences, or respective variants thereof having at least 70% homology, similarity or identity thereto, such as at least 80%, such as at least 90%, such as at least 91%, such as at least 92%, such as at least 93%, such as at least 94%, such as at least 95%, such as at least 96%, such as at least 97%, such as at least 98%, such as at least 99%, such as 100% homology, similarity or identity thereto.
  • the vector or system of vectors may comprise: i) splA, splB, splC, splD, splE, splF, splG, splH, and splI; ii) splA, splC, splD, splE, splF, splG, splH, splI, and splJ; iii) splA, splE, splF, splG, splH, splI, splJ, splK, and splL; P6215PC00 iv) splB, splD, splE, splG, splH, splI, splJ, splK, and splL;
  • said cell comprises ten of the above listed nucleic acid sequences, or respective variants thereof having at least 70% homology, similarity or identity thereto, such as at least 80%, such as at least 90%, such as at least 91%, such as at least 92%, such as at least 93%, such as at least 94%, such as at least 95%, such as at least 96%, such as at least 97%, such as at least 98%, such as at least 99%, such as 100% homology, similarity or identity thereto.
  • the vector or system of vectors may comprise: i) splA, splB, splC, splD, splE, splF, splG, splH, splI, and splJ; ii) splA, splC, splD, splE, splF, splG, splH, splI, splJ, and splK; iii) splA, splB, splE, splF, splG, splH, splI, splJ, splK, and splL; iv) splB, splD, splE, splF, splG, splH, splI, and s
  • said cell comprises eleven of the above listed nucleic acid sequences, or respective variants thereof having at least 70% homology, similarity or identity thereto, such as at least 80%, such as at least 90%, such as at least 91%, such as at least 92%, such as at least 93%, such as at least 94%, such as at least 95%, such as at least 96%, such as at least 97%, such as at least 98%, such as at least 99%, such P6215PC00 as 100% homology, similarity or identity thereto.
  • the vector or system of vectors may comprise: i) splA, splB, splC, splD, splE, splF, splG, splH, splI, splJ and splK; ii) splA, splC, splD, splE, splF, splG, splH, splI, splJ, splK, and splL; iii) splA, splB, splD, splE, splF, splG, splH, splI, splJ, splK, and splL; iv) splA, splB, splC, splE, spl
  • said cell comprises all the above listed nucleic acid sequences, or respective variants thereof having at least 70% homology, similarity or identity thereto, such as at least 80%, such as at least 90%, such as at least 91%, such as at least 92%, such as at least 93%, such as at least 94%, such as at least 95%, such as at least 96%, such as at least 97%, such as at least 98%, such as at least 99%, such as 100% homology, similarity or identity thereto.
  • the cell naturally comprises any one of the above mentioned nucleic acid sequences or respective variants thereof having at least 70% homology, similarity or identity thereto, but not all of said nucleic acid sequences, only the nucleic acid sequences not comprised in the naturally occurring cell needs to be introduced in said cell in order for the cell to produce a compound of formula (I) as described herein.
  • said cell is a microorganism.
  • said cell is a naturally occurring cell or an artificially modified cell, such as a modified insect cell, or such as a modified microorganism.
  • the cell is a cell which does not occur in nature, in particular the cell is engineered.
  • said cell is a microorganism in its naturally occurring form.
  • the cell is artificially modified to produce or to enhance the production of the compound.
  • the microorganism may belong to the genus Streptomyces or Allokutzneria, for example S. iranensis, S.
  • said cell producing any one of the compounds disclosed herein is S. iranensis.
  • Said microorganisms may be in their natural occurring form, or artificially modified to enhance the production of the compound.
  • said cell may be a naturally occurring cell, wherein the naturally occurring cell is not a S. iranensis cell.
  • said cell is a non-natural S. iranensis.
  • said cell is an artificially modified cell expressing one or more heterologous proteins selected from the group consisting of: i) splA as set forth in SEQ ID NO: 13; ii) splB as set forth in SEQ ID NO: 14; iii) splC as set forth in SEQ ID NO: 15; iv) splD as set forth in SEQ ID NO: 16; P6215PC00 v) splE as set forth in SEQ ID NO: 17; vi) splF as set forth in SEQ ID NO: 18; vii) splG as set forth in SEQ ID NO: 19; viii) splH as set forth in SEQ ID NO: 20; ix) splI as set forth in SEQ ID NO: 21; x) splJ as set forth in SEQ ID NO: 22; xi) splK as set forth in SEQ ID NO: 23; and xii)
  • said cell is an artificially modified cell expressing one or more of: i) splA as set forth in SEQ ID NO: 13 or a functional variant thereof having at least 70% sequence identity thereto; ii) splB as set forth in SEQ ID NO: 14 or a functional variant thereof having at least 70% sequence identity thereto; iii) splC as set forth in SEQ ID NO: 15 or a functional variant thereof having at least 70% sequence identity thereto; iv) splD as set forth in SEQ ID NO: 16 or a functional variant thereof having at least 70% sequence identity thereto; v) splE as set forth in SEQ ID NO: 17 or a functional variant thereof having at least 70% sequence identity thereto; vi) splF as set forth in SEQ ID NO: 18 or a functional variant thereof having at least 70% sequence identity thereto; vii) splG as set forth in SEQ ID NO: 19 or a functional variant thereof having at least 70% sequence identity thereto;
  • said cell is an artificially modified cell expressing splA as set forth in SEQ ID NO: 13 or a functional variant thereof having at least 70% sequence homology, or sequence identity thereto, such as at least 75%, such as at least 80%, such as at least 85%, such as at least 90%, such as at least 95% sequence homology, or sequence identity thereto.
  • said cell is an artificially modified cell expressing splB as set forth in SEQ ID NO: 14 or a functional variant thereof having at least 70% sequence homology, or sequence identity thereto, such as at least 75%, such as at least 80%, such as at least 85%, such as at least 90%, such as at least 95% sequence homology, or sequence identity thereto.
  • said cell is an artificially modified cell expressing splC as set forth in SEQ ID NO: 15 or a functional variant thereof having at least 70% sequence homology, or sequence identity thereto, such as at least 75%, such as at least 80%, such as at least 85%, such as at least 90%, such as at least 95% sequence homology, or sequence identity thereto.
  • said cell is an artificially modified cell expressing splD as set forth in SEQ ID NO: 16 or a functional variant thereof having at least 70% sequence homology, or sequence identity thereto, such as at least 75%, such as at least 80%, such as at least 85%, such as at least 90%, such as at least 95% sequence homology, or sequence identity thereto.
  • said cell is an artificially modified cell expressing splE as set forth in SEQ ID NO: 17 or a functional variant thereof having at least 70% homology, or sequence sequence identity thereto, such as at least 75%, such as at least 80%, such as at least 85%, such as at least 90%, such as at least 95% sequence homology, or sequence identity thereto.
  • said cell is an artificially modified cell expressing splF as set forth in SEQ ID NO: 18 or a functional variant thereof having at least 70% sequence homology, or sequence identity thereto, such as at least 75%, such as at least 80%, such as at least 85%, such as at least 90%, such as at least 95% homology, or sequence sequence identity thereto.
  • said cell is an artificially modified cell expressing splG as set forth in SEQ ID NO: 19 or a functional variant thereof having at least 70% sequence homology, or sequence identity thereto, such as at least 75%, such as at least 80%, such as at least 85%, such as at least 90%, such as at least 95% sequence homology, or sequence identity thereto.
  • said cell is an artificially modified cell expressing splH as set forth in SEQ ID NO: 20 or a functional variant thereof having at least 70% sequence homology, or sequence identity thereto, such as at least 75%, such as at least 80%, such as at least 85%, such as at least 90%, such as at least 95% sequence homology, or sequence identity thereto.
  • said cell is an artificially modified cell expressing splI as set forth in SEQ ID NO: 21 or a functional variant thereof having at least 70% sequence homology, or sequence identity thereto, such as at least 75%, such as at least 80%, such as at least 85%, such as at least 90%, such as at least 95% sequence homology, or sequence identity thereto.
  • said cell is an artificially modified cell expressing splJ as set forth in SEQ ID NO: 22 or a functional variant thereof having at least 70% sequence homology, or sequence identity thereto, such as at least 75%, such as at least 80%, such as at least 85%, such as at least 90%, such as at least 95% sequence homology, or sequence identity thereto.
  • said cell is an artificially modified cell expressing splK as set forth in SEQ ID NO: 23 or a functional variant thereof having at least 70% sequence identity thereto, such as at least 75%, such as at least 80%, such as at least 85%, such as at least 90%, such as at least 95% sequence homology, or sequence identity thereto.
  • said cell is an artificially modified cell expressing splL as set forth in SEQ ID NO: 24 or a functional variant thereof having at least 70% sequence homology, or sequence identity thereto, such as at least 75%, such as at least 80%, such as at least 85%, such as at least 90%, such as at least 95% sequence homology, or sequence identity thereto.
  • the cell may be modified to express any combination of: a) two of the above listed proteins; b) three of the above listed proteins; c) four of the above listed proteins; d) five of the above listed proteins; e) six of the above listed proteins; f) seven of the above listed proteins; g) eight of the above listed proteins; h) nine of the above listed proteins; i) ten of the above listed proteins; j) eleven of the above listed proteins; k) twelve of the above listed proteins; or functional variants thereof having at least 70% homology, or similarity or identity thereto, such as at least 80%, such as at least 90%, such as at least 91%, such as at least 92%, such as at least 93%, such as at least 94%, such as at least 95%, such as at least 96%, such as at least 97%, such as at least 98%, such as at least 99%, such as 100% homology, similarity or identity thereto.
  • two of the above listed genes have been introduced in the cell, or respective variants thereof having at least 70% homology, similarity or identity thereto, such as at least 80%, such as at least 90%, such as at least 91%, such as at least 92%, such as at least 93%, such as at least 94%, such as at least 95%, such as at least 96%, such as at least 97%, such as at least 98%, such as at least 99%, such as 100% homology, similarity or identity thereto.
  • the cell may express the proteins: i) splA and splB; ii) splA and splC; iii) splA and splD; P6215PC00 iv) splA and splE; v) splA and splF; vi) splA and splG; vii) splA and splH; viii) splA and splI; ix) splA and splJ; x) splA and splK; xi) splA and splL; or functional variants thereof having at least 70% homology, similarity or identity thereto, such as at least 80%, such as at least 90%, such as at least 91%, such as at least 92%, such as at least 93%, such as at least 94%, such as at least 95%, such as at least
  • three of the above listed genes have been introduced in the cell, or respective variants thereof having at least 70% homology, similarity or identity thereto, such as at least 80%, such as at least 90%, such as at least 91%, such as at least 92%, such as at least 93%, such as at least 94%, such as at least 95%, such as at least 96%, such as at least 97%, such as at least 98%, such as at least 99%, such as 100% homology, similarity or identity thereto.
  • the cell may express the proteins: i) splA, splB, splC; ii) splA, splC, and splD; iii) splA, splE, and splF; iv) splA, splG, and splH; v) splA, splI, and splJ; vi) splA, splK, and splL; vii) splA, splB, and splD; viii) splA, splC, and splF; ix) splA, splE, and splH; x) splA, splG, and splJ; xi) splA, splI, and splL
  • four of the above listed genes have been introduced in the cell, or respective variants thereof having at least 70% homology, similarity or identity thereto, such as at least 80%, such as at least 90%, such as at least 91%, such as at least 92%, such as at least 93%, such as at least 94%, such as at least 95%, such as at least 96%, such as at least 97%, such as at least 98%, such as at least 99%, such as 100% homology, similarity or identity thereto.
  • the cell may express the proteins: i) splA, splB, splC, and splD; ii) splA, splC, splD, and splE; iii) splA, splE, splF, and splG; iv) splA, splG, splH, and splI; v) splA, splI, splJ, and splK; vi) splA, splB, splK, and splL; vii) splA, splB, splD, and splF; viii) splA, splC, splF, and splE; ix) splA, splE, spl
  • five of the above listed genes have been introduced in the cell, or respective variants thereof having at least 70% homology, similarity or identity thereto, such as at least 80%, such as at least 90%, such as at least 91%, such as at least 92%, such as at least 93%, such as at least 94%, such as at least 95%, such as at least 96%, such as at least 97%, such as at least 98%, such as at least 99%, such P6215PC00 as 100% homology, similarity or identity thereto.
  • the cell may express the proteins: i) splA, splB, splC, splD, and splE; ii) splA, splC, splD, splE, and splG; iii) splA, splE, splF, splG, and splI; iv) splA, splG, splH, splI, and splK; v) splA, splI, splJ, splK, and splL; vi) splA, splB, splC, splK, and splL; vii) splA, splB, splC, splD, and splF; viii)
  • six of the above listed genes have been introduced in the cell, or respective variants thereof having at least 70% homology, similarity or identity thereto, such as at least 80%, such as at least 90%, such as at least 91%, such as at least 92%, such as at least 93%, such as at least 94%, such as at least 95%, such as at least 96%, such as at least 97%, such as at least 98%, such as at least 99%, such as 100% homology, similarity or identity thereto.
  • the cell may express the proteins: i) splA, splB, splC, splD, splE and splF; ii) splA, splC, splD, splE, splF, and splG; iii) splA, splE, splF, splG, splH, and splI; iv) splA, splG, splH, splI, splJ, and splK; v) splA, splB, splI, splJ, splK, and splL; vi) splA, splB, splC, splD, splK, and splL; vii)
  • seven of the above listed genes have been introduced in the cell, or respective variants thereof having at least 70% homology, similarity or identity thereto, such as at least 80%, such as at least 90%, such as at least 91%, such as at least 92%, such as at least 93%, such as at least 94%, such as at least 95%, such as at least 96%, such as at least 97%, such as at least 98%, such as at least 99%, such as 100% homology, similarity or identity thereto.
  • the cell may express the proteins: i) splA, splB, splC, splD, splE, splF and splG; ii) splA, splC, splD, splE, splF, splG, and splH; iii) splA, splE, splF, splG, splH, splI, and splJ; iv) splA, splG, splH, splI, splJ, splK, and splL; v) splA, splB, splC, splI, splJ, splK, and splL; vi) splA, splB,
  • P6215PC00 In some embodiments, eight of the above listed genes have been introduced in the cell, or respective variants thereof having at least 70% homology, similarity or identity thereto, such as at least 80%, such as at least 90%, such as at least 91%, such as at least 92%, such as at least 93%, such as at least 94%, such as at least 95%, such as at least 96%, such as at least 97%, such as at least 98%, such as at least 99%, such as 100% homology, similarity or identity thereto.
  • at least 70% homology, similarity or identity thereto such as at least 80%, such as at least 90%, such as at least 91%, such as at least 92%, such as at least 93%, such as at least 94%, such as at least 95%, such as at least 96%, such as at least 97%, such as at least 98%, such as at least 99%, such as 100% homology, similarity or identity thereto.
  • the cell may express the proteins: i) splA, splB, splC, splD, splE, splF, splG, and splH; ii) splA, splC, splD, splE, splF, splG, splH, and splI; iii) splA, splE, splF, splG, splH, splI, splJ, and splK; iv) splA, splB, splG, splH, splI, splJ, splK, and splL; v) splA, splB, splC, splG, splI, and
  • nine of the above listed genes have been introduced in the cell, or respective variants thereof having at least 70% homology, similarity or identity thereto, such as at least 80%, such as at least 90%, such as at least 91%, such as at least 92%, such as at least 93%, such as at least 94%, such as at least 95%, such as at least 96%, such as at least 97%, such as at least 98%, such as at least 99%, such as 100% homology, similarity or identity thereto.
  • the cell may express the proteins: i) splA, splB, splC, splD, splE, splF, splG, splH, and splI; ii) splA, splC, splD, splE, splF, splG, splH, splI, and splJ; iii) splA, splE, splF, splG, splH, splI, splJ, splK, and splL; P6215PC00 iv) splB, splD, splE, splG, splH, splI, splJ, splK, and splL; v)
  • ten of the above listed genes have been introduced in the cell, or respective variants thereof having at least 70% homology, similarity or identity thereto, such as at least 80%, such as at least 90%, such as at least 91%, such as at least 92%, such as at least 93%, such as at least 94%, such as at least 95%, such as at least 96%, such as at least 97%, such as at least 98%, such as at least 99%, such as 100% homology, similarity or identity thereto.
  • the cell may express the proteins: i) splA, splB, splC, splD, splE, splF, splG, splH, splI, and splJ; ii) splA, splC, splD, splE, splF, splG, splH, splI, splJ, and splK; iii) splA, splB, splE, splF, splG, splH, splI, splJ, splK, and splL; iv) splB, splD, splE, splF, splG, splH, splI, splJ,
  • eleven of the above listed genes have been introduced in the cell, or respective variants thereof having at least 70% homology, similarity or identity thereto, such as at least 80%, such as at least 90%, such as at least 91%, such as at least 92%, such as at least 93%, such as at least 94%, such as at least 95%, such as at least 96%, such as at least 97%, such as at least 98%, such as at least 99%, such as 100% homology, similarity or identity thereto.
  • the cell may express the proteins: P6215PC00 i) splA, splB, splC, splD, splE, splF, splG, splH, splI, splJ and splK; ii) splA, splC, splD, splE, splF, splG, splH, splI, splJ, splK, and splL; iii) splA, splB, splD, splE, splF, splG, splH, splI, splJ, splK, and splL; iv) splA, splB, splC, splE, s
  • all of the above listed genes have been introduced in the cell, or respective variants thereof having at least 70% homology, similarity or identity thereto, such as at least 80%, such as at least 90%, such as at least 91%, such as at least 92%, such as at least 93%, such as at least 94%, such as at least 95%, such as at least 96%, such as at least 97%, such as at least 98%, such as at least 99%, such as 100% homology, similarity or identity thereto.
  • the activity of variant can be measured by detecting the amount of compound of formula (I) synthesised, for example as described in the examples.
  • said cell is an artificially modified cell that comprises any of the disclosed nucleic acids.
  • said cell is an artificially modified cell that comprises any of the disclosed vectors or system of vectors.
  • said cell is employed to obtain compounds comprising a spiro- fused ring and a beta-lactone ring or a derivative thereof.
  • the compound is the compound of formula (I) as described herein or a salt or derivative thereof.
  • the compound is the compound of formula (II), preferably the compound of formula (III).
  • said cell can be provided directly to the animal or to the agricultural product, such as a plant, or the compound can be purified to some extent as described herein above.
  • said cell is supplied to the animal or to the agricultural product in the prophylaxis and/or treatment of an infection or a condition, wherein said infection or condition is caused by a microorganism as described herein.
  • the compound of formula (I) as described herein produced by the cell comprises a spiro-fused ring and a beta-lactone ring or a derivative thereof.
  • the compound is the compound of formula (II), preferably the compound of formula (III).
  • the disclosure is directed to the use of a cell as described herein for producing the compound of formula (I) as described herein.
  • P6215PC00 Examples Example 1 – General Experimental Procedures Strain fermentation and isolation. Streptomyces iranensis DSM 41954 was ordered from the German Collection of Microorganisms and Cell Cultures GmbH (DSMZ).
  • the strain was cultivated in medium 2 (CaCl 2 ⁇ 2H 2 O, 3.0 g; citric acid/Fe III, 1.0 g; MnSO 4 ⁇ H 2 O, 0.2 g; ZnCl 2 , 0.1 g; CuSO 4 ⁇ 5H 2 O, 0.025 g; Na 2 B 4 O 2 ⁇ 10H 2 O, 0.02 g; NaMoO 4 ⁇ 2H 2 O, 0.01 g; and oatmeal, 20.0 g, in 1.0 L distilled water), at 175 L scale in a 300 L fermentor vessel.
  • medium 2 CaCl 2 ⁇ 2H 2 O, 3.0 g; citric acid/Fe III, 1.0 g; MnSO 4 ⁇ H 2 O, 0.2 g; ZnCl 2 , 0.1 g; CuSO 4 ⁇ 5H 2 O, 0.025 g; Na 2 B 4 O 2 ⁇ 10H 2 O, 0.02 g; NaMoO 4 ⁇ 2H 2 O, 0.
  • the fermentation was carried out for 6 days with aeration of 25–50 L min –1 , stirring at 200 rpm with a temperature of 28 °C, and at a pH range of 5.4–6.4.
  • the fermentation broth was filtered and loaded onto an Amberchrom 161c resin LC column (200 ⁇ 20 cm, 6 L). Elution with a linear gradient of H2O–MeOH (from 30% to 100% v/v, flow rate 0.5 L min–1, in 58 min) afforded seven fractions (A–G).
  • Fraction G was firstly fractionated by silica gel chromatography with a CH2Cl2/CH3OH gradient to yield 16 fractions, F01-F16.
  • F07 was further separated by a Sephadex LH- 20 (MeOH) column, and twelve sub-fractions were obtained. The fourth sub-fraction was separated by HPLC RP-C 18 (AcCN/H 2 O as gradient) to afford spirolactone (5.3 mg).
  • Spirolactone white solid; [ ⁇ ] ⁇ ⁇ 6 (6.5 mg/mL, CH 3 OH), CD UV (CH 3 CN/H 2 O) ⁇ max 230, 270 nm; ECD ⁇ ext ( ⁇ ) (CH3OH) 235 (–9.78), 267 (7.02), 301 (–3.31) nm; IR (ATR) vmax 2932, 2748, 2704, 1810, 1713, 1686, 1619, 1457, 1382, 1173, 1134, 1085, 1057, 1013, 991, 947 cm -1 ; (+)-HRESIMS m/z 876.5112 [M + NH4] + (calcd for C47H70O14, 876.5104).
  • NMR spectra were recorded on 800 MHz Bruker Avance III spectrometer equipped with a TCI CryoProbe using standard pulse sequences. NMR data were processed using MestReNova 11.0.
  • UHPLC-HRMS was performed on an Agilent Infinity 1290 UHPLC system equipped with a diode array detector. UV-Vis spectra were recorded from 190 to 640 nm. Specific rotations were acquired using Perkin-Elmer 241 polarimeter. ECD spectra were obtained on a JASCO J-1500 CD Spectrometer.
  • IR data were acquired on Bruker Alpha FTIR spectrometer using OPUS version 7.2.
  • X-ray TLC analysis was performed on silica gel plates (Sil G/UV254, 0.20 mm, Macherey- Nagel).
  • Biotage Isolera One Flash Chromatography system was used for flash chromatography and performed on silica gel 60 (Merck, 0.04–0.063 mm, 230–400 mesh ASTM).
  • Sephadex LH-20 was from Pharmacia. All solvents and chemicals used for HRMS and chromatography were VWR Chemicals LC-MS grade, while for metabolites extraction, the solvents were of HPLC grade (VWR Chemicals). Spirolactone was isolated as a white solid. HRMS confirmed its molecular formula as C47H70O14.
  • the 13 C NMR spectrum showed signals for an ester carbonyl C1 ( ⁇ 168.6), three keto- groups C12 ( ⁇ 207.3), C27 ( ⁇ 201.3) and C38 ( ⁇ 209.6) and two ester groups C40 ( ⁇ 161.8) and C47 ( ⁇ 174.9). Furthermore, signals were observed for six olefinic methines C2 ( ⁇ 128.5), C3 ( ⁇ 137.8), C4 ( ⁇ 129.1), C5 ( ⁇ 143.2), C28 ( ⁇ 123.0) and C29 ( ⁇ 156.4).
  • the present inventors To investigate its biosynthetic P6215PC00 pathway, the present inventors firstly examined its potential retro-biosynthesis, which indicated its biosynthesis via a hybrid of polyketide and fatty acid-derived units.
  • the unusual biosynthesis involves an incorporation of a beta-lactone starting unit and uptake of an acyl carboxylic acid chain via nucleophilic attack aided lactonization.
  • the proposed biosynthesis is shown in Figure 4.
  • the inventors carried out genome- mining using anti-SMASH.
  • nine modular type I PKS BGCs were predicted.
  • One PKS ( Figure 5) with 16 AT domains was proposed to be the core enzyme.
  • the identity of the biosynthetic gene cluster was confirmed with CRISPR-cas9 mutant on the core polyketide gene ( Figure 6).
  • Example 4 Spirolactone as a novel antifungal lead Minimal Inhibition Concentration (Table 3) of spirolactone was tested against eight test strains Aspergillus fumigatus IBT29089, Aspergillus niger IBT30071, Aspergillus flavus IBT30114, Aspergillus nidulans IBT23742, Aspergillus tubingensis IBT23488, Aspergillus terreus IBT6207, Alternaria solani IBT7718 and Alternaria solani As112.
  • Agar diffusion assay ( Figure 7) was tested against Aspergillus nidulans IBT23742, Aspergillus niger IBT30071 and Aspergillus flavus IBT30114. Results are shown in Table 3. Table 3. MIC values for spirolactone and amphotericin b. P6215PC00 The procedure was following the EUCAST standard method (EUCAST: MIC and zone distributions and ECOFFs - https://www.eucast.org/mic_distributions_and_ecoffs/). Amphotericin b was used as a positive control. The test strains were derived from DTU Bioengineering fungal IBT culture collection of fungi.
  • AntiSMASH 5.0 Updates to the Secondary Metabolite P6215PC00 Genome Mining Pipeline. Nucleic Acids Research 2019. https://doi.org/10.1093/nar/gkz310. 3. Horn, F.; Schroeckh, V.; Netzker, T.; Guthke, R.; Linde, J. Draft Genome Sequence of Streptomyces iranensis. Genome Announcements 2014. https://doi.org/10.1128/genomeA.00616-14. 4. Bode, H. B.; Bethe, B.; Höfs, R.; Zeeck, A. Big Effects from Small Changes: Possible Ways to Explore Nature’s Chemical Diversity. ChemBioChem 2002, 3 (7), 619–627.
  • OLEX2 A Complete Structure Solution, Refinement and Analysis Program. Journal of Applied Crystallography, 42, 339-341. http://dx.doi.org/10.1107/S0021889808042726. 9. Sheldrick, G.M. (2015). Acta Cryst. A71, 3-8. https://doi.org/10.1107/S2053229614024218. P6215PC00 10. Sheldrick, G.M. (2015). Acta Cryst. C71, 3-8. https://doi.org/10.1107/S2053273314026370.
  • P6215PC00 Items 1 An isolated nucleic acid comprising or consisting of a nucleic acid selected from the group consisting of: i) splA as set forth in SEQ ID NO: 1; ii) splB as set forth in SEQ ID NO: 2; iii) splC as set forth in SEQ ID NO: 3; iv) splD as set forth in SEQ ID NO: 4; v) splE as set forth in SEQ ID NO: 5; vi) splF as set forth in SEQ ID NO: 6; vii) splG as set forth in SEQ ID NO: 7; viii) splH as set forth in SEQ ID NO: 8; ix) splI as set forth in SEQ ID NO: 9; x) splJ as set forth in SEQ ID NO: 10; xi) splK as set forth in SEQ ID NO: 11; and xii)
  • a vector or a system of vectors comprising any one of the isolated nucleic acids selected from the group consisting of: i) splA as set forth in SEQ ID NO: 1; ii) splB as set forth in SEQ ID NO: 2; iii) splC as set forth in SEQ ID NO: 3; iv) splD as set forth in SEQ ID NO: 4; v) splE as set forth in SEQ ID NO: 5; vi) splF as set forth in SEQ ID NO: 6; vii) splG as set forth in SEQ ID NO: 7; viii) splH as set forth in SEQ ID NO: 8; ix) splI as set forth in SEQ ID NO: 9; x) splJ as set forth in SEQ ID NO: 10; P6215PC00 xi) splK as set forth in SEQ ID NO: 11; and xii)
  • vector or system of vectors comprising any combination of two or more isolated nucleic acids selected from the group consisting of: i) splA as set forth in SEQ ID NO: 1; ii) splB as set forth in SEQ ID NO: 2; iii) splC as set forth in SEQ ID NO: 3; iv) splD as set forth in SEQ ID NO: 4; v) splE as set forth in SEQ ID NO: 5; vi) splF as set forth in SEQ ID NO: 6; vii) splG as set forth in SEQ ID NO: 7; viii) splH as set forth in SEQ ID NO: 8; ix) splI as set forth in SEQ ID NO: 9; x) splJ as set forth in SEQ ID NO: 10; xi) splK as set forth in SEQ ID NO: 11;
  • vector or system of vectors according to any one of items 2-3, wherein the vector or system of vectors comprises all the isolated nucleic acids: i) splA as set forth in SEQ ID NO: 1; ii) splB as set forth in SEQ ID NO: 2; iii) splC as set forth in SEQ ID NO: 3; iv) splD as set forth in SEQ ID NO: 4; P6215PC00 v) splE as set forth in SEQ ID NO: 5; vi) splF as set forth in SEQ ID NO: 6; vii) splG as set forth in SEQ ID NO: 7; viii) splH as set forth in SEQ ID NO: 8; ix) splI as set forth in SEQ ID NO: 9; x) splJ as set forth in SEQ ID NO: 10; xi) splK as set forth in SEQ ID NO: 11; and
  • a cell such as a non-natural cell, expressing one or more heterologous proteins selected from the group consisting of: i) splA as set forth in SEQ ID NO: 13; ii) splB as set forth in SEQ ID NO: 14; iii) splC as set forth in SEQ ID NO: 15; iv) splD as set forth in SEQ ID NO: 16; v) splE as set forth in SEQ ID NO: 17; vi) splF as set forth in SEQ ID NO: 18; vii) splG as set forth in SEQ ID NO: 19; viii) splH as set forth in SEQ ID NO: 20; ix) splI as set forth in SEQ ID NO: 21; x) splJ as set forth in SEQ ID NO: 22; xi) splK as set forth in SEQ ID NO: 23; and xii) splL
  • the cell according to item 5 wherein the cell is a non-natural cell, expressing one or more heterologous proteins selected from the group consisting of: i) splA as set forth in SEQ ID NO: 13; P6215PC00 ii) splB as set forth in SEQ ID NO: 14; iii) splC as set forth in SEQ ID NO: 15; iv) splD as set forth in SEQ ID NO: 16; v) splE as set forth in SEQ ID NO: 17; vi) splF as set forth in SEQ ID NO: 18; vii) splG as set forth in SEQ ID NO: 19; viii) splH as set forth in SEQ ID NO: 20; ix) splI as set forth in SEQ ID NO: 21; x) splJ as set forth in SEQ ID NO: 22; xi) splK as set forth in SEQ ID NO: 23;
  • splA as set forth in SEQ ID NO: 13 or a functional variant thereof having at least 70% sequence identity thereto
  • splB as set forth in SEQ ID NO: 14 or a functional variant thereof having at least 70% sequence identity thereto
  • splC as set forth in SEQ ID NO: 15 or a functional variant thereof having at least 70% sequence identity thereto
  • splD as set forth in SEQ ID NO: 16 or a functional variant thereof having at least 70% sequence identity thereto
  • splE as set forth in SEQ ID NO: 17 or a functional variant thereof having at least 70% sequence identity thereto
  • vi) splF as set forth in SEQ ID NO: 18 or a functional variant thereof having at least 70% sequence identity thereto
  • vii) splG as set forth in SEQ ID NO: 19 or a functional variant thereof having at least 70%
  • the cell comprises any one of the nucleic acid sequences selected from the group consisting of: i) splA as set forth in SEQ ID NO: 1; ii) splB as set forth in SEQ ID NO: 2; iii) splC as set forth in SEQ ID NO: 3; iv) splD as set forth in SEQ ID NO: 4; v) splE as set forth in SEQ ID NO: 5; vi) splF as set forth in SEQ ID NO: 6; vii) splG as set forth in SEQ ID NO: 7; viii) splH as set forth in SEQ ID NO: 8; ix) splI as set forth in SEQ ID NO: 9; x) splJ as set forth in SEQ ID NO: 10; xi) splK as set forth in SEQ ID NO: 11; and xii)
  • the microorganism belongs to the genus Streptomyces or Allokutzneria, for example S. iranensis, S.
  • a method for the prophylaxis and/or treatment of an infection or a condition comprising administering a compound comprising: P6215PC00 a spiro-fused ring; and a beta-lactone ring, or a derivative thereof, such as an acceptable derivative thereof, wherein said infection or condition is caused by a microorganism.
  • a cell for producing the compound of any one of items 13-14 preferably wherein the cell is a Streptomyces cell such as a Streptomyces iranensis cell, wherein the cell is as defined in any one of items 5-12. 18.
  • Use of a cell capable of producing the compound of any one of items 13-14 in a method for preventing growth of a microorganism on a surface or a plant preferably wherein the cell is a Streptomyces cell such as a Streptomyces iranensis cell, preferably wherein the cell is as defined in any one of times 5- 12. 19.
  • R5 is methoxy. 33.
  • the minimal inhibition concentration of the compound for the microorganism causing the condition is at least 2-fold, at least 3-fold, at least 5-fold, at least 10-fold, at least 20-fold, at least 30-fold, at least 40-fold, at least 50-fold, at least 60-fold, at least 70-fold, at least 80-fold, at least 90-fold, at least 100-fold, at least 110-fold, at least 120-fold, at least 130-fold, at least 140-fold, at least 150-fold, at least 160-fold, at least 170-fold, at least 180-fold, at least 190-fold, at least 200-fold lower than Amphoterin B towards a microorganism of the same species.
  • P6215PC00 71 The compound, the compound for the use, the method, or the use of a compound or of a cell according to any one of items 63-65 or 67, wherein the Aspergillus belongs to Section Circumdati; Section Flavi; or Section Nigri.
  • the Aspergillus is selected from the group consisting of: Aspergillus fumigatus; Aspergillus niger; Aspergillus flavus; Aspergillus nidulans; and Aspergillus tubingensis.
  • Alternaria is selected from the group consisting of: Alternaria solani; Alternaria alternate; Alternaria arborescens; Alternaria arbusti; Alternaria blumeae; Alternaria brassicae; Alternaria brassicicola; Alternaria burnsii; Alternaria carotiincultae; Alternaria carthami; Alternaria celosiae; Alternaria cinerariae; Alternaria citri; Alternaria conjuncta; Alternaria cucumerina; Alternaria dauci; Alternaria dianthi; Alternaria dianthicola; Alternaria eichhorniae; Alternaria euphorbiicola; Alternaria gaisen; Alternaria helianthi; Alternaria helianthicola; Alternaria hungarica; Alternaria infect
  • Botrytis is selected from the group consisting of: Botrytis cinerea; Botrytis aclada; Botrytis allii; Botrytis allii-fistulosi; Botrytis ampelophila; Botrytis P6215PC00 anacardii; Botrytis anthophila; Botrytis argillacea; Botrytis arisaemae; Botrytis artocarpi; Botrytis bifurcate; Botrytis bryi; Botrytis capsularum; Botrytis carnea; Botrytis cinerea; Botrytis aclada; Botrytis allii; Botrytis allii-fistulosi; Botrytis ampelophila; Botrytis P6215PC00 anacardii; Botrytis anthophila; Botrytis argillacea; Botrytis arisaemae; Botrytis artocarpi
  • Staphylococcus is selected from the group consisting of: Staphylococcus aureus; Staphylococcus argenteus; Staphylococcus aureus; Staphylococcus schweitzeri; Staphylococcus simiae; Staphylococcus auricularis; Staphylococcus carnosus; Staphylococcus condiment; Staphylococcus debuckii; Staphylococcus massiliensis; Staphylococcus piscifermentans; Staphylococcus simulans; Staphylococcus capitis; Staphylococcus caprae; Staphylococcus epidermidis; Staphylococcus saccharolyticus; Staphylococcus borealis; Staphylococcus devriesei; Staphylococcus
  • the Staphylococcus is a Staphylococcus aureus.
  • Staphylococcus argenteus Staphylococcus aureus
  • Staphylococcus aureus Staphylococcus schweitzeri
  • Staphylococcus simiae 82.
  • P6215PC00 91.
  • the compound, the compound for the use, the method, or the use of a compound or of a cell according to any one of items 84, 86 or 91, wherein the agricultural product is selected from the group consisting of: almond; anemone; apple; apricot; asparagus; avocado; azalea; banana; beet; bell pepper; blueberry; broccoli; cabbage; caneberries; canola; carrot; cereal; coffee; cherries; chickpea; cole crops; cocoa; corn; cotton; cucumber; date palm; Dianthus; Dracena; eggplant; figs; ginseng; garlic; gourd; grape; grapefruit; grapevine; horseradish; hot pepper; leek; legumes; lemon; lentil; lettuce; lime; mango; melon; nut; oil seed rape; onion; orange; palm oil; papaya; parsley; parsnip; pea; peach; peanut; pear; pineapple; pistachio; pomelo; potato; pumpkin; raisins; sesame seeds; squash; soybean;
  • the microorganism producing the compound is supplied as dried solid spores at a concentration between 0.1 and 150x10 9 spores/mL, between 0.1 and 200x10 9 spores/mL, between 0.1 and 10x10 9 spores/mL, between 0.1 and 20x10 9 spores/mL, between 0.1 and 30x10 9 spores/mL, between 0.1 and 40x10 9 spores/mL, P6215PC00 between 0.1 and 50x10 9 spores/mL, between 0.1 and 60x10 9 spores/mL, between 0.1 and 70x10 9 spores/m
  • a method of disinfecting a surface comprising a microorganism such as a pathogenic microorganism comprising contacting a compound comprising: a spiro-fused ring; and a beta-lactone ring, or a derivative thereof, with the surface. 104.
  • the method according to item 103 wherein the compound has formula or is a salt or solvate thereof; wherein, R 4 is independently selected from the group consisting of: hydrogen, alkyl and halogen; R 1 , R 2 and R 3 is selected from the group consisting of: hydrogen; oxo; hydroxy; and methoxy; R 5 is selected from the group consisting of hydrogen; alkyl; halogen; oxo; hydroxy; methoxy; and formula (IV): P6215PC00 105.
  • the method according to item 104 wherein the compound has formula (II): or is a salt or solvate thereof.
  • 106 The method according to any one of items 104-105, wherein R 1 is hydroxyl. 107.
  • the compound is administered wherein the compound is administered between 0.05 and 1 mg of the compound/kg of a recipient, between 0.05 and 2 mg/kg, between 0.05 P6215PC00 and 3 mg/kg, between 0.05 and 4 mg/kg, between 0.05 and 5 mg/kg, between 0.05 and 6 mg/kg, between 0.05 and 7 mg/kg, between 0.05 and 8 mg/kg, between 0.05 and 9 mg/kg, between 0.05 and 10 mg/kg, between 0.06 and 1 mg/kg, between 0.06 and 2 mg/kg, between 0.06 and 3 mg/kg, between 0.06 and 4 mg/kg, between 0.06 and 5 mg/kg, between 0.06 and 6 mg/kg, between 0.06 and 7 mg/kg, between 0.06 and 8 mg/kg, between 0.06 and 9 mg/kg, between 0.06 and 10 mg/kg, between 0.06 and mg/kg, between 0.07 and 1 mg/kg, between 0.07 and 2 mg/kg, between 0.07 and 3 mg/kg, between 0.07 and
  • P6215PC00 121 The method according to any one of items 103-120, wherein the minimal inhibition concentration of the compound for disinfecting the surface is lower than 100 ⁇ g/mL, lower than 90 ⁇ g/mL, lower than 80 ⁇ g/mL, lower than 70 ⁇ g/mL, lower than 60 ⁇ g/mL, lower than 50 ⁇ g/mL, lower than 40 ⁇ g/mL, lower than 30 ⁇ g/mL, lower than 20 ⁇ g/mL, lower than 15 ⁇ g/mL, lower than 10 ⁇ g/mL, lower than 5 ⁇ g/mL, lower than 3 ⁇ g/mL, lower than 1 ⁇ g/mL. 122.
  • the Aspergillus is selected from the group consisting of: Aspergillus fumigatus; Aspergillus niger; Aspergillus flavus; Aspergillus nidulans; and Aspergillus tubingensis, Aspergillus alliaceus; Aspergillus arachidicola; Aspergillus carbonarius; Aspergillus clavatus; Aspergillus felis; Aspergillus flavipes; Aspergillus japonicas; Aspergillus lentulus; Aspergillus minisclerotigens; Aspergillus mottae; Aspergillus nomius; Aspergillus parasiticus; Aspergillus ochraceus; Aspergillus terreus; Aspergillus transmontanensi; Aspergillus sergii; Aspergillus steynii; Asperg
  • Alternaria is selected from the group consisting of: Alternaria solani; Alternaria alternate; Alternaria arborescens; Alternaria arbusti; Alternaria blumeae; Alternaria brassicae; Alternaria brassicicola; Alternaria burnsii; Alternaria carotiincultae; Alternaria carthami; Alternaria celosiae; Alternaria cinerariae; Alternaria citri; Alternaria conjuncta; Alternaria cucumerina; Alternaria dauci; Alternaria dianthi; Alternaria dianthicola; Alternaria eichhorniae; Alternaria P6215PC00 euphorbiicola; Alternaria gaisen; Alternaria helianthi; Alternaria helianthicola; Alternaria hungarica; Alternaria infectoria; Alternaria japonica; Alternaria limicola; Alternaria
  • Staphylococcus is selected from the group consisting of: Staphylococcus aureus; Staphylococcus argenteus; Staphylococcus aureus; Staphylococcus schweitzeri; Staphylococcus simiae; Staphylococcus auricularis; Staphylococcus carnosus; Staphylococcus condiment; Staphylococcus debuckii; Staphylococcus massiliensis; Staphylococcus piscifermentans; Staphylococcus simulans; Staphylococcus capitis; Staphylococcus caprae; Staphylococcus epidermidis; Staphylococcus saccharolyticus; Staphylococcus borealis; Staphylococcus devriesei; Staphylococcus haemolyticus; Staphylococcus hominis; Staphylococcus
  • Staphylococcus is selected from the group consisting of: Staphylococcus aureus; Staphylococcus argenteus; Staphylococcus aureus; Staphylococcus schweitzeri; and Staphylococcus simiae.
  • the Staphylococcus is a Staphylococcus aureus.
  • the compound is formulated as a gel, as a spray, or as a wipe.
  • the use or the method according to any one of items 102-145, wherein the compound is comprised within a composition. 147.
  • the use or the method according to item 146, wherein the composition further comprises an acceptable carrier.
  • the composition further comprises at least one other disinfectant, such as a disinfectant against Gram-negative bacteria.
  • the composition further comprises at least one other antifungal agent.
  • P6215PC00 150 The use or the method according to any one of items 146-149, wherein the composition further comprises at least one other antibiotic. 151.
  • composition further comprises at least one other bactericidal agent.
  • composition further comprises at least one degreasing agent, a fragrance, or both.
  • the subject is an animal as defined in any one of items 84, 85, 87-90.
  • the subject is an agricultural product as defined in any one of items 84, 86, 91-93.

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Abstract

La présente invention concerne, de manière générale, des bêta-lactones comprenant un cycle spiro-fusionné et un cycle bêta-lactone et des dérivés associés, en particulier un macrolide inédit appelé spirolactone, et leur utilisation comme agents antimicrobiens.
PCT/EP2023/067953 2022-06-30 2023-06-30 Spirolactone comme nouvelle tête de série antimicrobienne Ceased WO2024003331A1 (fr)

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AU2023301447A AU2023301447A1 (en) 2022-06-30 2023-06-30 Spirolactone as a novel antimicrobial lead
EP23736344.5A EP4547243A1 (fr) 2022-06-30 2023-06-30 Spirolactone comme nouvelle tête de série antimicrobienne
CA3259968A CA3259968A1 (fr) 2022-06-30 2023-06-30 Spirolactone comme nouvelle tête de série antimicrobienne

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WO2025146463A1 (fr) * 2024-01-03 2025-07-10 Danmarks Tekniske Universitet Nouvelles cellules de streptomyces modifiées produisant de l'alligamycine a avec des rendements plus élevés

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2025146463A1 (fr) * 2024-01-03 2025-07-10 Danmarks Tekniske Universitet Nouvelles cellules de streptomyces modifiées produisant de l'alligamycine a avec des rendements plus élevés

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