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WO2016051767A1 - Antibiotiques antibactériens à spectre étroit ciblant des types spécifiques de bactérie qui permet de synthétiser de la ménaquinone par voie alterne par le biais de futalosine ou 6-aminodéoxyfutalosine en tant qu'intermédiaire - Google Patents

Antibiotiques antibactériens à spectre étroit ciblant des types spécifiques de bactérie qui permet de synthétiser de la ménaquinone par voie alterne par le biais de futalosine ou 6-aminodéoxyfutalosine en tant qu'intermédiaire Download PDF

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WO2016051767A1
WO2016051767A1 PCT/JP2015/004928 JP2015004928W WO2016051767A1 WO 2016051767 A1 WO2016051767 A1 WO 2016051767A1 JP 2015004928 W JP2015004928 W JP 2015004928W WO 2016051767 A1 WO2016051767 A1 WO 2016051767A1
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futalosine
siamycin
pathway
acid
fatty acid
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Satoshi Omura
Hidenori MATSUI
Hirofumi Nakano
Tsuyoshi Yamamoto
Kenzaburo YAMAJI
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Kitasato Institute
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Kitasato Institute
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    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23B—PRESERVATION OF FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES; CHEMICAL RIPENING OF FRUIT OR VEGETABLES
    • A23B2/00—Preservation of foods or foodstuffs, in general
    • A23B2/70—Preservation of foods or foodstuffs, in general by treatment with chemicals
    • A23B2/725—Preservation of foods or foodstuffs, in general by treatment with chemicals in the form of liquids or solids
    • A23B2/729—Organic compounds; Microorganisms; Enzymes
    • A23B2/762—Organic compounds containing nitrogen
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23B—PRESERVATION OF FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES; CHEMICAL RIPENING OF FRUIT OR VEGETABLES
    • A23B2/00—Preservation of foods or foodstuffs, in general
    • A23B2/70—Preservation of foods or foodstuffs, in general by treatment with chemicals
    • A23B2/725—Preservation of foods or foodstuffs, in general by treatment with chemicals in the form of liquids or solids
    • A23B2/729—Organic compounds; Microorganisms; Enzymes
    • A23B2/7295—Antibiotics
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23L—FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES, NOT OTHERWISE PROVIDED FOR; PREPARATION OR TREATMENT THEREOF
    • A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
    • A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
    • A23L33/127—Antibiotics
    • 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
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/20—Carboxylic acids, e.g. valproic acid having a carboxyl group bound to a chain of seven or more carbon atoms, e.g. stearic, palmitic, arachidic acids
    • 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
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/20—Carboxylic acids, e.g. valproic acid having a carboxyl group bound to a chain of seven or more carbon atoms, e.g. stearic, palmitic, arachidic acids
    • A61K31/201—Carboxylic acids, e.g. valproic acid having a carboxyl group bound to a chain of seven or more carbon atoms, e.g. stearic, palmitic, arachidic acids having one or two double bonds, e.g. oleic, linoleic acids
    • 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
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/20—Carboxylic acids, e.g. valproic acid having a carboxyl group bound to a chain of seven or more carbon atoms, e.g. stearic, palmitic, arachidic acids
    • A61K31/202—Carboxylic acids, e.g. valproic acid having a carboxyl group bound to a chain of seven or more carbon atoms, e.g. stearic, palmitic, arachidic acids having three or more double bonds, e.g. linolenic
    • 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
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
    • A61K38/12—Cyclic peptides, e.g. bacitracins; Polymyxins; Gramicidins S, C; Tyrocidins A, B or C
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/164—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from bacteria
    • 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

Definitions

  • the present invention relates to treatment or prevention of bacterial infection by using narrow-spectrum antibacterial antibiotics. Specifically, the present invention relates to antibiotics against bacteria that synthesizes menaquinone (also known as vitamin K2, hereinafter abbreviated to "MK") through an alternative pathway via futalosine or 6-aminodeoxyfutalosine as an intermediate (hereinafter referred to as the futalosine pathway).
  • MK menaquinone
  • MK 6-aminodeoxyfutalosine
  • Narrow-spectrum antibiotics are active against a selected group of bacteria and have advantages to avoid the evolution of drug resistance and super-infection, overgrowth of pathogens after treatment by broad-spectrum antibiotics.
  • fidaxomicin a narrow-spectrum antibiotic
  • fidaxomicin has shown selective eradication of pathogenic Clostridium difficile with minimal disruption to the multiple species of bacteria that make up the normal, healthy intestinal flora. The maintenance of normal physiological conditions in the colon can reduce the probability of Clostridium difficile infection recurrence.
  • Campylobacter and Helicobacter species are frequently associated with human hosts. Campylobacter jejuni causes of diarrheal disease in humans, and it also infects in the intestinal tracts of many livestock, especially poultry (Newell (2002). Int. J. Infect Dis. 6, 3S16-3S21). Helicobacter pylori (hereinafter abbreviated to "H. pylori”) infects in the human stomach, and this infection causes many gastric diseases, including gastric carcinoma (Cover & Blaser (2009) Gastroenterol. 136, 1863-1873).
  • H. pylori gastric diseases, including gastric carcinoma (Cover & Blaser (2009) Gastroenterol. 136, 1863-1873).
  • H. pylori is a Gram-negative bacterium that infects approximately half of the world's human population. H. pylori infection is considered an important factor in the pathogenesis of gastric diseases, gastric cancer, gastric ulcer, chronic gastritis, peptic ulcer disease, gastric adenocarcinoma, and gastric B-cell mucosa-associated lymphoid tissue lymphoma in humans (Kusters et al. (2006) Clin. Microbiol. Rev. 19, 449-490.; Cover & Blaser (2009) Gastroenterol. 136, 1863-1873; Wroblewski et al. (2010) Clin. Microbio.l Rev. 23, 713-739).
  • H. pylori There is a first-line chemotherapy for the eradication of H. pylori, which consists of 7-14 days of three standard agents: a proton pump inhibitor, plus any two of the antibiotics, amoxillin, clarithromycin, and metronidazole (Chey & Wong (2007) Am. J. Gastroenterol. 102, 1808-1825; Rimbara et al. (2011) Nat. Rev. Gastroenterol. Hepatol. 8, 79-88); Malfertheiner et al. (2012) Gut 61, 646-664; Tsukanov et al. (2013) J. Antibiot. (Tokyo) 48, 433-434); Yuan et al. (2013) Cochrane. Database. Syst. Rev.
  • MK is an obligatory component of the electron-transfer system in prokaryotes (Kurosu & Begari (2010) Molecules 15, 1531-1553).
  • the MK biosynthetic pathway derived from chorismate through o-succinyl benzoate via 8 enzymes has mainly been studied in Escherichia coli. (Bentley & Meganathan (1982) Microbiol Rev 46, 241-280). Recently, genomic analyses have revealed an alternative MK biosynthetic pathway (the futalosine pathway) derived from chorismate in specific bacteria, including H.
  • H. pylori 26695, B38, B8, G27, HPAG1, J99, P12, PeCan4, SJM180, and Shi470
  • H. acinonychis SHeeba H. felis ATCC 49179, H. hepaticus ATCC 51449, H. mustelae 12198, H. bizzozeronii CIII-1, H. heilmannii s.s. ASB1.4, and H. suis (HS1, HS5, TKY (unpublished data of ours), and SNTW101 (unpublished data of ours)) and 11 Campylobacter strains, namely, C.
  • 5'-methylthioadenosine nucleosidase is implicated in playing a key role in modified futalosine pathway (i.e., chorismate -> 6-amino-6-deoxyfutalosine -> dehypoxanthinyl futalosine -> cyclic dehypoxantine futalosine -> 1,4-dihydroxy-6-naphthoic acid -> MK).
  • Siamycin I is also known to exert antimicrobial activity against Gram-positive bacteria, but does not inhibit the growth of Gram-negative bacteria, including Escherichia coli, Klebsiella pneumoniae, Citrobacter freundii, Salmonella typhi, and Pseudomonas aeruginosa (Tsunakawa et al. (1995) J. Antibiot. (Tokyo) 48, 433-434).
  • This highly constrained lasso structure of this compound (16-21 amino acids in length, with an N-terminal cyclized ring and a C-terminal tail that share a slipknot-like structure) is extremely resistant to thermal, chemical, and proteolytic degradation (Maksimov et al. (2012) Nat. Prod. Rep.
  • Siamycin I has been shown to directly inhibit the autophosphorylation activity of the FsrC quorum sensor of Enterococcus faecalis (Ma et al. (2011) FEBS Lett. 585, 2660-2664). Synchrotron radiation circular spectroscopy revealed that the binding of siamycin I to FsrC exerts a significant effect on the local tertiary structures of the TyR and Trp resides of the protein and/or peptide ligands (gelatinase biosynthesis-activating pheromone) and siamycin I (Phillips-Jones et al. (2013) Phys. Chem. Chem. Phys. 15, 444-447).
  • siamycin I showed antimicrobial activity against Kitasatospora setae KM-6054 T at lower concentration than the concentration which shows antibacterial activity against Bacillus subtilis H17 by the paper disc method.
  • Siamycin I showed in vitro anti-H. pylori activity, and the compound and two fatty acids decreased the number of infected bacteria in a mouse model.
  • fatty acids have anti-Helicobacter effect. However, they never had inhibitory effects on the futalosine pathway.
  • the inventors screened to find fatty acids that inhibit a futalosine pathway and discovered only 13 strains from 6,183 strains. Although the remaining strains also produced fatty acids, they were not potent inhibitiors targeting the futalosine pathway.
  • the present invention provides selected fatty acids as a novel antibacterial agent, which inhibits H. pylori to growth in vitro and to colonize on the gastric mucosa in a mouse model. Meanwhile, it was previously demonstrated that some free fatty acids can inhibit up to 50% of H. pylori growth in vitro within a concentration of 1 mM, whereas 2 mM would kill all bacteria.
  • Aseanostatin P5 as fatty acid was already known to inhibit myeloperoxidase release from human polymorphonuclear leukocytes (Kitahama et al. (1995) Biosci. Biotech. Biochem., 59, 78-82). Tanaka et al. also found that aseanostatin P5 (12-methyltetradecanoic acid, reminderc acid) inhibits the futalosine pathway (Tanaka et al. (2011) J. Antibiot. 64, 151-153). However, those mechanisms are not becoming apparent. In past times, Khulusi et al. propounded the idea that fatty acids inhibit the growth of H.
  • fatty acids such as aseanostatin P5, eicosapentaenoic acid (hereinafter abbreviated to "EPA”), arachidonic acid, and docosahexaenoic acid (hereinafter abbreviated to "DHA”) inhibit the futalosine pathway to exert antimicrobial effect.
  • EPA eicosapentaenoic acid
  • DHA docosahexaenoic acid
  • EPA and DHA showed significant eradication effect as has been reported also in our experiment.
  • the fatty acids exhibited slightly stronger effect than simaycin I although, since the concentration of siamycin I was lower than that of fatty acids, the value of siamycin I might be superior in eliminating H. pylori.
  • Siamycin I and some lasso peptides are not sensitive to the degradation by some proteases, based on their structure. (Maksimov et al. (2012) Nat. Prod. Rep. 29, 996-1006).
  • the present invention provides the use of EPA, DHA, and siamycin I for the treatment or prevention of H. pylori infection. If the subject had been fed a diet deficient in MK, the treatments with EPA, DHA, and siamycin I might have conferred stronger protection against the gastric colonization of H. pylori.
  • the futalosine pathway is a fitted target for development of specific narrow-spectrum agents. This is because human and common intestinal bacteria lack this pathway. It had been revealed that H. pylori and Campylobacter have alternative MK biosynthetic pathway by whole genome sequences analysis (Apel et al. (2012) J. Bacteriol. 194, 2342-2354; Kim et al. (2014) Acta. Crystallogr. D. Biol. Crystallogr. 70, 177-185). The inventors started the screening of 6,183 culture broth samples in order to find compounds that can inhibit the futalosine pathway.
  • the inventors isolated the known lasso peptide, siamycin I, from the culture broth of Streptomyces sp. K12-1112. In this study, the inventors describe the isolation, structure elucidation and in vitro/in vivo activity of siamycin I.
  • the inventors conducted an agar plate assay to select new narrow-spectrum antibiotics targeting the futalosine pathway of MK biosynthesis, which is essential for limited group of bacteria such as Helicobacter, Campylobacter and Streptomyces.
  • the inventors identified a lasso peptide antibiotic (siamycin I) and certain polyunsaturated fatty acids as new narrow-spectrum agents that can inhibit the selected group of bacteria in which MK is synthesized through the futalosine pathway and then the supplementation with MK emulsion rescued the bacterial growth.
  • the antibacterial polyunsaturated fatty acids include ingredients of foods, such as linolenic acids, EPA and DHA, and the effective concentration is lower than the safe range with no toxic effects in published studies.
  • the present invention includes a lasso peptide antibiotic (siamycin I) and certain omega-3 and omega-6 polyunsaturated fatty acids as specific inhibitors targeting the futalosine pathway based on the finding that siamycin I, EPA, and DHA suppressed the gastric colonization of H. pylori in mice.
  • the present invention includes following inventions: (1) A method for the treatment or prevention of bacterial infections or the diseases caused by bacterial infections in a subject comprising administration of siamycin I or a fatty acid to the subject, wherein the bacterium synthesize menaquinone through the futalosine pathway, and wherein the siamycin I or a fatty acid inhibits the futalosine pathway. (2) The method of (1), wherein the bacterium is selected from a group consisting of genus of Helicobacter, Campylobacter, Wolinella and Streptomyces.
  • bacterium is a Helicobacter pylori
  • fatty acid is at least one fatty acid that is selected from a group consisting of omega-3 fatty acids, ⁇ -linolenic acid, EPA, DHA, Oleic acid, linoleic acid, and arachidonic acid.
  • the bacterium is selected from a group consisting of genus of Helicobacter, Campylobacter, Wolinella and Streptomyces.
  • the method of (5), wherein the bacterium is a Helicobacter pylori.
  • fatty acid is at least one fatty acid that is selected from a group consisting of omega-3 fatty acids, ⁇ -linolenic acid, EPA, DHA, Oleic acid, linoleic acid, and arachidonic acid.
  • a pharmaceutical composition comprising siamycin I or a fatty acid for use in treatment or prevention of bacterial infections or the diseases caused by bacterial infections in a subject, wherein the bacterium synthesize menaquinone through the futalosine pathway, and wherein the siamycin I or a fatty acid inhibits the futalosine pathway in the treatment or prevention of bacterial infections or the diseases caused by bacterial infections in a subject.
  • a pharmaceutical composition comprising siamycin I or a fatty acid for use in inhibiting synthesis of menaquinone through the futalosine pathway by bacteria in a subject who is infected by the bacteria comprising administration of siamycin I or a fatty acid to the subject, wherein the bacteria synthesize menaquinone through the futalosine pathway, and wherein the siamycin I or a fatty acid can inhibit the futalosine pathway.
  • the pharmaceutical composition of (9) or (10), wherein the bacterium is a Helicobacter pylori.
  • Siamycin I or a fatty acid for inhibiting synthesis of menaquinone through the futalosine pathway by a bacterium in a subject who is infected by the bacterium comprising administration of siamycin I or a fatty acid to the subject, wherein the bacteria synthesize menaquinone through the futalosine pathway, and wherein the siamycin I or a fatty acid inhibits the futalosine pathway.
  • the present invention is directed to a method for the treatment or prevention of bacterial infections and/or the diseases caused by bacterial infections in a subject comprising administration of siamycin I or a fatty acid to the subject, wherein the bacteria synthesizes MK through the futalosine pathway.
  • the siamycin I or the fatty acid inhibits the futalosine pathway, so that inhibits the growth of a bacterium.
  • the present invention relates to a pharmaceutical composition comprising siamycin I or a fatty acid for use in a treatment or a prevention of a disease, disorder or condition caused by, associated with or accompanied by an bacterial infection, in a subject, wherein the bacteria synthesizes MK through the futalosine pathway and the siamycin I or the fatty acid inhibit the futalosine pathway.
  • the present invention is directed to a method of inhibiting synthesis of MK through the futalosine pathway in bacteria.
  • the present invention includes a method of prevention or treatment of bacterial infection by administering an pharmaceutically effective amount of siamycin I or a fatty acid to the subject in need thereof, wherein the bacteria synthesis MK through the futalosine pathway and the siamycin I or the fatty acid inhibits the futalosine pathway.
  • the present invention furhter includes a food, feedstuff or drinking water containing siamycin I or a fatty acid, that is resistant to bacterium that synthesize menaquinone through the futalosine pathway.
  • siamycin I or a fatty acid should be artificially added to the food and food containing siamycin I or a fatty acid as natural nutrient is not included in the invention.
  • the food, feedstuff or drinking water can be in the form of supplement or food additives.
  • the food, feedstuff or drinking water containing siamycin I or a fatty acid is resistant to the bacterium which synthesize menaquinone through the futalosine pathway, and thus can be used for prevention of infection and propagation of the bacterium.
  • Amino acid sequence (21-residue lasso peptide) of the compound isolated from the culture broth of Streptomyces sp. K12-1112 (molecular weight, 2163.5; exact mass, 2161.8518).
  • Polysaturated fatty acids and siamycin I effects on H. pylori infection in mice. Effects of EPA, DHA, and siamycin I on H. pylori infection in mice.
  • mice Six-week old female C57BL/6 mice were supplemented with EPA (31.3 ⁇ g/ml, 103 ⁇ M), DHA (31.3 ⁇ g/ml, 95 ⁇ M), siamycin I (5.4 ⁇ g/ml, 2.5 ⁇ M), or not supplemented (0.01% ethanol, control) in the drinking water 1 week before the infection with 1 x 10 8 colony-forming units (hereinafter abbreviated to "c.f.u. “) of H. pylori SS1 over the experimental period. Mice were orally infected with H. pylori Sydney strain 1 (hereinafter abbreviated to "SS1”) twice with a two-day interval (A).
  • ALA Alpha-linoleic acid
  • GLA gamma-linoleic acid
  • 250 mg/l, 898 ⁇ M, EPA 250 mg/l, 826 ⁇ M
  • DHA 250 mg/l, 761 ⁇ M
  • siamycin I 10 mg/l, 4.6 ⁇ M
  • elaidic acid 200 mg/l, 708 ⁇ M
  • Shown are the combined results from 4 independent experiments. Data represent the mean ⁇ standard deviation (n 4). The mean values of different groups (control versus supplementation with siamycin I or elaidic acid) were examined using a two-tailed unpaired Student’s t-test. P ⁇ 0.05 was regarded as statistically significant. ND, not detected.
  • the "futalosine pathway” is a MK biosynthetic pathway in which MK is synthesized from chorismate via futalosine or 6-aminodeoxyfutalosine as an intermediate.
  • Bacteria that synthesis MK through the futalosine pathway include genus of Helicobacter such as Helicobacter heilmannii sensu stricto, Helicobacter heilmannii sensu lato, and H. pylori, genus of Campylobacter, genus of Wolinella and genus of Streptomyces.
  • bacteria that synthesis MK through the futalosine pathway does not excludes bacteria that can synthesis MK through the canonical MK biosynthetic pathway, however the bacteria describing here should synthesis MK mostly through the futalosine pathway but less through the canonical MK biosynthetic pathway under the specific condition.
  • the specific condition means a condition wherein the bacteria infect mammals and contribute to onset or aggravation of the diseases caused by bacterial infection.
  • the specific condition can be the condition that the bacteria are incubated during the selection test or determination.
  • the bacteria that synthesis MK through the futalosine pathway may include Bacillus subtilis, Staphylococcus aureus, Micrococcus luteus, Mycobacterium smegmatis, Escherichia coli, Pseudomonas aeruginosa, Xanthomonas campestris, Bacteroides fragilis, Acholeplasma laidlawii, Candida albicans, Saccharomyces cerevisiae, Aspergillus niger, Pyricularia oryzae, Mucor racemosus, Campylobacter jejuni, Thermus thermophilus, Wolinella succinogenes, Streptomyces coelicolor, Helicobacter heilmannii sensu stricto, Helicobacter heilmannii sensu lato, and H. pylori.
  • siamycin I means a 21-residue tricyclic peptide of amino acids sequence of CLGVGSCNDFAGCGYAIVCFW having structure of Figure 1.
  • the siamycin I can be prepared by conventional method as described in the publications(Tsunakawa et al. (1995) J Antibiot (Tokyo) 48, 433-434; Nakayama et al. (2007) J. Bacteriol. 189, 1358-1365)..
  • a fatty acid means a polyunsaturated fatty acid, which can inhibit the synthesis of MK through the futalosine pathway in the bacteria that synthesis MK through the futalosine pathway, other than aseanostatin P5 and aseanostatin P6.
  • Such polyunsaturated fatty acids include omega-3 fatty acids ( ⁇ -linolenic acid, EPA and DHA), Oleic acid, linoleic acid, and arachidonic acid. Whether a polyunsaturated fatty acid can inhibit the synthesis of MK through the futalosine pathway in the bacteria that synthesis MK through the futalosine pathway or not can be determined by the paper-disc agar-plate method with indicator.
  • paper disks containing test fatty acid are placed on at least two agar plates seeded the bacteria that synthesis MK through the futalosine pathway, wherein at least one plate contains MK and the other plate(s) do not contain MK. Then, the plates are incubated under the condition that is suitable for growth of the bacteria. After incubation, inhibition of growth of the bacteria (antimicrobial activities) are measured as the inhibitory zone diameter (mm). When the inhibitory zone is appeared and the growth of the bacteria is inhibited in the plates not supplemented with MK but the inhibition is not detected in the plates supplemented with MK, the test fatty acid is determined as the fatty acid which can inhibit synthesis of MK through the futalosine pathway in the bacteria.
  • peptides or the fatty acids can be administered in a form of their respective pharmaceutically active salts.
  • Suitable pharmaceutically active salts comprise acid addition salts and alkali or earth alkali salts.
  • the peptides form pharmaceutically acceptable salts with organic and inorganic acids.
  • suitable acids for such acid addition salt formation are hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, acetic acid, citric acid, oxalic acid, malonic acid, salicylic acid, p-aminosalicylic acid, malic acid, fumaric acid, succinic acid, ascorbic acid, maleic acid, sulfonic acid, phosphoric acid, perchloric acid, nitric acid, formic acid, propionic acid, gluconic acid, lactic acid, tartaric acid, hydroxymaleic acid, pyruvic acid, phenylacetic acid, benzoic acid, p-aminobenzoic acid, p-hydroxybenzoic acid, methanesulfonic acid, ethanesulfonic acid, nitrous acid, hydroxyethanesulfonic acid, ethylenesulfonic acid, p-toluenesulf
  • the peptides or the fatty acids also form pharmaceutically acceptable salts with organic and inorganic bases.
  • suitable bases for such acid addition salt formation are trometamol, trimethylamine, dimethylamine, ethylamine, triethylamine, diethylamine, L-lysine, L-arginine, diethanolamine, sodium hydroxide, calcium hydroxide, sodium hydroxide, potassium hydroxide, lithium hydroxide and the like; alkaline earth metal bases, such as calcium hydroxide, barium hydroxide and the like; and ammonium hydroxide.
  • Alkali metal or alkaline earth metal salts suitable for forming pharmaceutically acceptable salts can include anions such as carbonates, bicarbonate and sulfates. For instance, sodium, potassium, lithium, magnesium or calcium salts can be obtained.
  • the salts are prepared by contacting the free base form with a sufficient amount of the desired acid to produce a salt in the conventional manner.
  • the diseases caused by bacteria refers to any disease, wherein the prior infection with the bacteria that synthesis MK through the futalosine pathway is causative for the development of the disease. This applies also to diseases, wherein the infection with bacteria promotes the formation of the disease, without being the primary factor for the disease.
  • Such disease includes gastroduodenitis, atrophic gastritis, nodular gastritis, chronic gastritis, erosive gastritis, reflux esophagitis and gastritis, idiopathic thrombocytopenic purpura (IPT), gastric ulcer, duodenal ulcer, hyperplasia, mucosa associated lymphoma tissue (MALT) lymphoma, diffuse large B-cell lymphoma, and duodenal and gastric adenocarcinoma.
  • IPT idiopathic thrombocytopenic purpura
  • MALT mucosa associated lymphoma tissue lymphoma
  • diffuse large B-cell lymphoma diffuse large B-cell lymphoma
  • duodenal and gastric adenocarcinoma duodenal and gastric adenocarcinoma.
  • Administration forms of the pharmaceutical composition include, for example, pills, tablets, film tablets, coated tablets, capsules, liposomal formulations, micro- and nano-formulations, powders and deposits in the form of gels, elixirs, dispersible granules, syrups, suspensions, creams, lotions, solutions, emulsions, suspensions, dispersions, and the like.
  • the present invention also includes pharmaceutical preparations for parenteral application, including dermal, intradermal, intragastral, intracutan, intravasal, intravenous, intramuscular, intraperitoneal, intranasal, intravaginal, intrabuccal, percutan, rectal, subcutaneous, sublingual, topical, or transdermal application, which preparations in addition to typical vehicles and/or diluents contain the peptide.
  • Preparation of the pharmaceutical composition of the present invention can be achieved by using a conventional method by using pharmaceutically acceptable carriers, excipients and/or diluents, such as lactose, starch, sucrose, cellulose, magnesium stearate, dicalcium phosphate, calcium sulfate, talc, mannitol, ethyl alcohol (liquid filled capsules), gelatin, corn sweeteners, gums such as acacia, sodium alginate, carboxymethyl- cellulose, polyethylene glycol and waxes, boric acid, sodium benzoate, sodium acetate, sodium chloride, water or water-propylene glycol solutions, sugars such as lactose, sucrose, mannitol and sorbitol, starches derived from wheat, corn rice and potato, and celluloses such as microcrystalline cellulose, and if necessary by using a conventional used adjuvant at suitable dosage level in a known way.
  • the peptides are suitable for intravenous administration or suitable for oral administration or suitable for administration by inhalation.
  • the present invention relates to a method for the treatment of a disease, disorder or condition caused by, associated with or accompanied by an bacterial infection, comprising administering a pharmaceutically effective amount of siamycin I or pharmaceutical composition comprising siamycin I to a subject in need thereof, wherein the bacteria synthesizes MK through the futalosine pathway.
  • a pharmaceutically effective amount refers to the effective provision of protection effects to prevent, inhibit, or arrest the symptoms and/or progression of a disease caused by the bacteria.
  • a pharmaceutically effective amount means a sufficient amount of the peptides of the invention to produce a therapeutic effect, as defined above, in a subject or patient in need of treatment.
  • subject' or patient mean any mammal, including but not limited to human beings, including a human patient or subject to which the compositions of the invention can be administered.
  • mammals include human patients and non-human primates, as well as experimental animals such as swine, cats, dogs, rabbits, rats, and mice, and other animals.
  • the pharmaceutical composition or the siamycin I or the fatty acids can be administered solely or in combination with other agents.
  • the other agents includes, anti-inflammatory drugs and antibacterial agents.
  • the dose and regimen of the pharmaceutical composition or the siamycin I or the fatty acids of the invention are adjusted depending on factors such as the amount required, therapeutic method, type of disease and degree of necessity of each subject to be treated. Specifically, the dose can be determined depending on the age, body weight, general state of health, sex, diet, the time and route of administration, excretion rate, combination of pharmaceutical agent, and disease state of a patient; other factors can be taken into consideration as well.
  • siamycin I or the fatty acids is administered subcutaneously, intravenously, intramuscularly or rectally at a dose of approximately 0.01-100 mg/person/day as siamycin I or the fatty acids, preferably at 0.1-50 mg/person/day; and for oral administration, siamycin I or the fatty acids is administered at a dose of approximately 0.01-500 mg/person/day, preferably at 0.1-100 mg/person/day.
  • Oleic acid, stearic acid, linoleic acid, and arachidonic acid were purchased from Sigma Aldrich.
  • EPA, DHA, linoleic acid (both ⁇ -linoleic acid and ⁇ -linoleic acid) was purchased from Cayman chemical.
  • MK (0.2% emulsified powder) was provided from Kyowa Hakko Bio Co., Ltd. Screening samples was provided from Kitasato University Institute for Life Science.
  • Bacillus halodurans C-125 was obtained from Japan Agency for Marine-earth Science and Technology.
  • Bacillus subtilis H17 was obtained from Japan National Institute of Genetics.
  • Streptomyces avermitilis SUKA17 was stored in Kitasato University Institute for Life Science.
  • NMR and ESI-MS Nuclear magnetic resonance (hereinafter abbreviated to “NMR”) spectra were measured on a Varian XL-400 spectrometer with 1 H NMR at 400 MHz (Agilent Technologies, Santa Clara, CA).
  • ESI-MS electrospray ionization-mass spectrometry
  • Kitasatospora setae KM-6054T, Bacillus halodurans C-125, or Bacillus subtilis H17 was grown on 1.0% agar plates containing 1.0% glucose and 1.0% yeast extract for 24 h at 27 °C, 1.5% agar plates containing 1.7% tryptone, 0.3% soytone, 0.25% dextrose, 0.5% NaCl, and 0.25% K 2 HPO 4 for 24 h at 37 °C, or 0.8% agar plates containing 0.5% yeast extract, 0.5% polypeptone, 2.0% NaCl, 20 mg/l L-tryptophan, 20 mg/l L-arginine, and 1 mg/l phenol red for 15 h at 37 °C, respectively.
  • pylori SS1 was grown on Helicobacter-selective agar plates (Nissui Pharmaceutical) for 3 days in a humidified incubator with the desired gas mixture (5% O 2 , 10% CO 2 , and 85% N 2 ) at 37 °C (Matsui et al. (2014) Helicobacter 19, 260-271).
  • mice were bred in the animal facility at the Kitasato Institute, and all mouse experiments were performed in accordance with institutional ethical guidelines under an approved study protocol (approval number, 13-011).
  • Actinomyces strain K12-1112 Actinomyces strain K12-1112 was isolated from aggregate of soil particle sample by using sonication-fracturing method (Matsumoto et al. (2006) Actinomycetol, 20, 30-34), collected in Japan. From the results of partial sequence analysis, K12-1112 strain was identified as a Streptomyces specie
  • the inventors employed a paper disc method to screen samples that show antimicrobial activity against Kitasatospora setae KM-6054 T , and not show the activity against Bacillus subtilis H17.
  • Media for each microorganism are as follows: a medium composed of 1.0% glucose, 1.0% yeast extract and 1.0% agar for Kitasatospora setae KM-6054T; a medium composed of 0.5% yeast extract, 0.5% polypeptone, 2.0% NaCl, 20 mg/l L-tryptophan, 20 mg/l L-arginine, 1 mg/l phenol red and 0.8% agar for Bacillus subtilis H17.
  • Paper discs (6 mm diameter; Advantec, Tokyo, Japan) containing samples was placed on an agar plate seeded with a test microorganism.
  • Kitasatospora setae KM-6054T was incubated for 24 hours at 27°C.
  • Bacillus subtilis H17 was incubated for 15 h at 37°C.
  • Antimicrobial activity was expressed as diameter of inhibitory zone.
  • MK (Vitamin K2 KYOWA, 0.2% emulsion powder) was kindly gifted from Kyowa Hakko Bio. Co., Ltd (Tokyo, Japan).
  • Kitasatospora setae KM-6054 T was recovered by supplement with MK (10 ⁇ g/disk).
  • MK 10 ⁇ g/disk
  • the 6,183 (2,160 fungi, 3,783 actinomycetes, and 240 Lactobacilli) microbial culture broths of actinomycetes and fungi were tested, a culture broth of Streptomyces sp. K12-1112 strain showed desired activity.
  • a 1 ml portion of the seed culture was transferred to each of 30 x 500-ml Erlenmeyer flasks containing 100 ml of the production medium (2.0% soluble starch, 0.5% glycerol, 1.0% defatted wheat germ, 0.3% meat extract, 0.3% dry yeast, and 0.3% CaCO 3 ).
  • Fermentation of Streptomyces sp. K12-1112 (30 x 100 ml in a 500-ml Erlenmeyer flask) was carried out on a rotary shaker at 210 rpm for 3 days at 27 °C, and was terminated by dilution with an equal volume of ethanol before filtration with paper (Advantec) to remove the precipitate.
  • the crude compound (siamycin I) was eluted with a 1:1 mixture of chloroform-methanol (yield, 348 mg), and then purified by preparative high performance liquid chromatography with a Senshu Pak preparative C18 Pegasil ODS SP100 column (20 x 150 mm) (Senshu Scientific, Tokyo, Japan) using 50% acetonitrile and 0.1% trifluoroacetic acid at a flow rate of 8 mL per min with ultraviolet detection at 210 nm (yield, 24 mg). Isolated compound was dissolved in 80% benzene and 20% methanol, and then added TMSCHN2. The mixture was reacted for 30 min at room temperature.
  • the reactant was dissolved in pylorridine, and added acetic acid. Then the mixture was reacted in 100°C, 30 min. The reactant was dissolved in dichloromethane, and washed with 5% HCl. The reactant was analyzed by EI-MS. All solvents (ethyl acetate, chloroform, methanol and acetonitrile) were purchased from Kanto Chemical.
  • Futalosine pathway inhibiting activity of siamycin I (1) Paper disc method with indicator bacteria. Antimicrobial activity of siamycin I was evaluated by paper disc method and summarized in Table 1. Paper discs (6 mm diameter) containing test samples were placed on agar plates seeded with Bacillus halodurans C-125 (2 x 10 2 spores/ml), Kitasatospora setae KM-6054T (1 x 10 4 spores/ml), or Bacillus subtilis H17 (2 x 10 2 spores/ml) and incubated for 15 h at 37 °C, 24 h at 27 °C, or 15 h at 37 °C, respectively.
  • test samples were supplemented with 5 mg of 0.2% MK emulsified powder (Kyowa Hakko).
  • the antimicrobial activities were expressed as the mean diameters (mm) of the zones of inhibition.
  • Alpha-linoleic acid hereinafter abbreviated to “ALA”
  • GLA gamma-linoleic acid
  • AdA arachidonic acid
  • EPA EPA
  • DHA DHA
  • elaidic acid the 9-trans isomer of oleic acid
  • fatty acids were purchased from Cayman Chemical or Sigma-Aldrich except for aseanostatin P5 (sarcinic acid) and aseanostatin P6 (laboratory stock; Sugita et al., (2013) The 133 rd Annual Meeting of Pharmaceutical Society of Japan, L0914B, March 27, Yokohama, Japan).
  • Siamycin I (1 ⁇ g/6 mm paper disc) and MK (Vitamin K2 KYOWA, 0.2% emulsion powder) (equivalent of 10 ⁇ g/6 mm paper disc of MK) were applied on the paper disc, and tested antimicrobial activity against Kitasatospora setae KM-6054 T .
  • Kitasatospora setae KM-6054 T was able to glow in the presence of siamycin I supplemented with MK. This result suggested that siamycin I inhibited the futalosine pathway of Kitasatospora setae KM-6054 T (Table 1).
  • the bacterial culture started from 1 x 10 5 c.f.u./ml, was diluted in phosphate buffered saline containing 0.01% gelatin, pH 7.4 (BSG; 1/10,000 and 1/100,000), and streaked 100 ⁇ l from each dilution on Helicobacter-selective agar plates to enumerate c.f.u.
  • mice were orally inoculated H. pylori SS1 with 1 x 10 8 c.f.u. twice at a two-day interval, and the mice were sacrificed 2 weeks after final infection.
  • the library of natural chemical compounds and fresh microbial cultures in Kitasato Institute of Biological Science were screened to find selective antibacterial activity for microorganisms that grow depend on the futalosine pathway.
  • the paper disks (6 mm diameter) were evaporated with the test samples, and then these paper discs set on the plate.
  • Bacillus halodurans C-125 and Bacillus subtilis H17 was incubated for 24 h at 37 °C.
  • Kitasatospora setae KM-6054 was incubated for 24 h at 30 °C. After static culture, the diameter of inhibitory zone was measured.
  • cis-unsaturated fatty acids specifically inhibit non-canonical MK biosynthetic pathway.
  • Oleic and palmitoleic acids are thought to inhibit phosphorylation of ATP to ADP in the histidine kinase activation. They occur naturally in human, animal and plant fat and do not inhibit bacterial growth. This activity was discovered in a kinase involved in sporulation named sensor protein kinase KinA of Bacillus subtilis.
  • the mode of action of cis unsaturated fatty acids is not known, except that they inhibit KinA ⁇ ATP binding in a non competitive fashion with an IC 50 (half maximal 50% inhibitory concentration) of around 20 ⁇ M.
  • Oleic acid is a component of mycobacterial media (OADC, oleic acid, albumin, dextrose complex), and must be broken down by the bacteria as an energy source, so its inhibitory activity may only act at a certain concentration, or in a particular arrangement of the fatty acid. Oleic acid has also been described as an uncoupler of mitochondrial oxidative phosphorylation and an activator of protein kinase C. The full extent of its activity on phosphorylation reactions in mycobacteria is unknown.
  • omega-3 and omega-6 polysaturated fatty acids including ALA, GLA, AdA, EPA, and DHA, inhibited the growth of Bacillus halodurans C-125 but not the growth of Bacillus subtilis H17, and the growth of Bacillus halodurans C-125 was recovered by supplementation with MK, suggesting that omega-3 and omega-6 polyunsaturated fatty acids had inhibitory activities targeting the futalosine pathway.
  • Caprylic acid, capric acid, and stearic acid which are saturated fatty acid, were no activity against the growth of Bacillus halodurans C-125.
  • aseanostatin P5 and P6 have activity of futalosine pathway inhibitor (Tanaka et al. (2011) J. Antibiot. (Tokyo), 64, 151-153), nevertheless they are saturated fatty acids.
  • Saturated fatty acids such as butyric acid, caproic acid, caprylic acid, palmitic acid is not effective on the inhibition of the futalosine pathway.
  • unsaturated fatty acids such as DHA, AdA, EPA, aALA, GLA, and linoleic acid are effective on the inhibition of the futalosine pathway.
  • oleic acid, linoleic acid, ⁇ -linolenic acid, arachidonic acid, eicosapenaenoic acid, and docosahexaenoic acid were active. They are active against B. halodurans C-125, but negative against Bacillus subtilis H17. Oleic acid was active, whreas elaidic acid was not . The difference between oleic acid and elaidic acid is their configuration. Oleic acid is cis-fatty acid and elaidic acid is trans-fatty acid. And oleic acid was inferior to linoleic acid, and ⁇ -linolenic acid.
  • oryzae KB88 Bacteroides fragilis KB169 (ATCC23745), Acholeplasma laidlawii KB174 (PG8), Candida albicans KF1, Saccharomyces cerevisiae KF237 (ATCC9763), Aspergillus niger KF103 (ATCC6275), Pyricularia oryzae KF180, Mucor racemosus KF223 (IFO4581). All microorganisms was tested by paper disc methods, and sample concentration was 10 ⁇ g/ml).
  • Aseanostatin P5 wasn’t effective against most microorganisms, both 10 ⁇ g per disc. As compared with aseanostatin P5, arachidonic acid and EPA have small effect against Bacillus subtilis KB211, and Streptococcus aureus KB210. But they are very small effect compared to the effect against Bacillus halodurans.
  • the bacterial culture started from 1 x 10 5 c.f.u./ml, was diluted in PBS (pH 7.4) containing 0.01% (w/v) gelatin (BSG) (1:10,000 and 1:100,000), and 0.1 ml from each dilution was streaked onto Helicobacter-selective agar plates for the enumeration of c.f.u.
  • ALA, GLA, EPA, DHA, siamycin I, and elaidic acid (the 9-trans isomer of oleic acid; used as the negative control) on H. pylori SS1 growth are shown in Figure 2.
  • ALA, GLA, EPA, DHA, and elaidic acid significantly inhibited the H. pylori SS1 growth (P ⁇ 0.05).
  • ALA 250 mg/l, 898 ⁇ M
  • GLA 250 mg/l, 898 ⁇ M
  • EPA 250 mg/l, 826 ⁇ M
  • DHA 250 mg/l, 761 ⁇ M
  • Siamycin I (10 mg/l, 4.6 ⁇ M) and even elaidic acid (200 mg/l, 708 ⁇ M) inhibited the H. pylori SS1 growth by 91% and 37%, respectively.
  • ALA, GLA, AdA, and EPA at concentrations of 200 ⁇ M or more, and DHA at concentrations of 85 ⁇ M or more, drastically inhibited the H. pylori growth (data not shown).

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Abstract

Selon l'invention, une voie alterne de synthèse biologique de la ménaquinone par le biais de futalosine ou 6-aminodéoxyfutalosine en tant qu'intermédiaire (voie de futalosine) est une cible d'intérêt pour de nouveaux agents antimicrobiens à spectre étroit. De la siamycine I et des acides gras ont été fournis en tant qu'activité antimicrobienne sélective contre des bactéries telles que Helicobacter et Campylobacter, qui dépendent de la voie de futalosine pour se développer. Plus précisément, la siamycine I et les acides gras polyinsaturés omega-3 inhibent la colonisation de H. pylori in vivo et, de ce fait, la siamycine I et les acides gras polyinsaturés omega-3 pourraient être un nouvel antibiotique à spectre étroit pour Helicobacter et Campylobacter.
PCT/JP2015/004928 2014-09-30 2015-09-29 Antibiotiques antibactériens à spectre étroit ciblant des types spécifiques de bactérie qui permet de synthétiser de la ménaquinone par voie alterne par le biais de futalosine ou 6-aminodéoxyfutalosine en tant qu'intermédiaire Ceased WO2016051767A1 (fr)

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