WO2024209060A1 - Polyaminated fatty acids for use as potentiators of antibacterial activity - Google Patents

Abstract

The present invention relates to the use of a polyaminated fatty acid compound responding to formula (I), a pharmaceutically acceptable salt and/solvate thereof, as an adjuvant to an antibacterial drug, a pharmaceutical composition comprising at least said polyaminated fatty acid compound and at least one antibacterial drug, said pharmaceutical composition for use as a medicament, said pharmaceutical composition for use in the treatment of bacterial or infectious diseases, in particular caused by Gram-negative bacteria, said pharmaceutical composition for use in killing or inhibiting the growth of persister cells, a kit comprising a composition comprising said polyaminated fatty acid compound, and a separate pharmaceutical composition comprising at least one antibacterial drug, and a polyaminated fatty acid compound responding to formula (I'-a), a pharmaceutically acceptable salt and/solvate thereof.

Description

POLYAMINATED FATTY ACIDS FOR USE AS POTENTIATORS OF

ANTIBACTERIAL ACTIVITY

The present invention relates to the use of a polyaminated fatty acid compound responding to formula (I), a pharmaceutically acceptable salt and/or solvate thereof, as an adjuvant to an antibacterial drug, a pharmaceutical composition comprising at least said polyaminated fatty acid compound and at least one antibacterial drug, said pharmaceutical composition for use as a medicament, said pharmaceutical composition for use in the treatment of bacterial or infectious diseases, in particular caused by Gram-negative bacteria, said pharmaceutical composition for use in killing or inhibiting the growth of persister cells, a kit comprising a composition comprising said polyaminated fatty acid compound, and a separate pharmaceutical composition comprising at least one antibacterial drug, and a specific polyaminated fatty acid compound responding to formula (I'-a), a pharmaceutically acceptable salt and/solvate thereof.

There is an increasing number of immunocompromised populations at risk of serious infections. These populations include people over 65 years of age, neonates, diabetics, chemotherapy patients and surgical patients, both in hospitals worldwide and in the community. These populations are the most likely to contract serious infections. The most common hospital-acquired infections are pneumonia and urinary tract infections (UTIs), which can be caused by infection with many different bacterial species. Pneumoniae infections account for 15% of all nosocomial infections and for 24% of infections acquired in intensive care units. Among the most common nosocomial infections, severe pneumonia has the highest mortality rate among hospital- acquired infections and is the 6^th leading cause of death, as well as the leading cause of sepsis.

The current situation of serious hospital-acquired infections is alarming, as some have become untreatable with current drugs due to the emergence of new pathogens with increased and insurmountable antibiotic resistance. Indeed, the massive and repeated use of antibiotics in human and animal health, whether in the city or in hospitals, as well as their misuse (e.g. treatments that are too short, too long or at inappropriate doses), have led to the appearance of resistant strains of bacteria to these antibiotics. Resistance was initially sporadic but has become massive and worrying. Multidrug resistance (MDR) is a phenomenon attributed to various mechanisms expressed in the same bacterial strain against different families of antibiotics. In February 2017, the WHO published a list of antibiotic-resistant "priority pathogens" representing the greatest threat to human health. The most critical group of pathogens includes multidrug resistant bacteria that pose a particular threat in hospitals, nursing homes, and among patients whose care requires devices such as ventilators and blood catheters. Such bacteria include Acinetobacter, Pseudomonas and various Enterobacteriaceae (including Klebsiella, E. coll, Serratia, and Proteus). They can cause severe and often deadly infections such as bloodstream infections and pneumonia.

These resistant strains have become particularly prevalent and deadly in Europe, United States of America, Africa and Asia, contributing to the significant incidence and mortality rates of hospital acquired infections (HAIs). To treat these nosocomial infections and improve the likelihood of adequate antibiotic coverage, current hospital guidelines generally recommend treating pneumonia with a combination of antibiotics. Although treating the infection with more than one antibiotic is effective in reaching many different bacterial targets, these guidelines provide only a temporary solution to the problem of antibiotic resistance and will ultimately cause more harm, as increased antibiotic use will only fuel the evolution of more widespread antibiotic resistance.

In addition to Hospital-acquired infection and antibiotic resistance, particularly in Gram-negative bacteria, there is a daunting and extremely critical unmet medical need, as R&D and federal approval of antibiotics are declining. New treatment strategies are thus needed to improve antibiotic efficacy and/or reduce resistance mechanisms. National and international health agencies have put in place a series of measures to encourage the control of drug use and the development of new molecules specifically for the treatment of Gram-negative bacteria. The low permeability of these bacteria, which are surrounded by an outer membrane that reduces diffusion of compounds, and the constitutive expression of efflux pumps (protein complexes that actively transport toxic molecules out of the cell) by these bacteria contribute to the low number of new active molecules. Furthermore, it is well documented that they can overproduce these efflux pumps in response to extracellular compounds, including drugs. Historically, the improvement of antibiotic activity has been largely achieved by varying the design of the pioneering bioactive molecules. Since the 1980s, new classes of antibiotics have emerged, although they have been mainly active against Gram-positive bacteria. Recent target-based high- throughput screening programmes, as well as in silico studies, have led to the identification of high potential hits. Although this strategy seems attractive, the main drawback of target-based assays is that they do not take into account membrane translocation barriers, which include bacterial permeation and efflux pump problems.

For several years, researchers have investigated the use one or more compounds devoid of antimicrobial activity to preserve existing antibiotics and potentiate their action. These peculiar compounds are called "adjuvants". The concept of antibiotic adjuvants deals with the ability of a molecule to potentiate and improve the effect of an antibiotic against a resistant microbial agent. Also called "resistance circuit breakers", "chemosensitizers" or "antibiotic potentiators", adjuvants are compounds without antimicrobial activity, although they can exert a slight inhibitory action of bacterial growth. In short, one can consider that once co-administered with an antibiotic, they "suppress" the resistance and "improve" the inhibitory effect.

For example, the international application WO2021/211123 Al describes tryptamine ureas and derivatives as adjuvants to sensitize gram-negative bacteria to the effects of polymyxin antibiotics such as colistin. Combination therapy of polymyxin antibiotics and the adjuvants has utility in the treatment of gram-negative bacterial infection, including treatment of drug-resistant strains.

Besides, drug resistance does not represent the only obstacle to efficacy of existing antibiotics. Indeed, even high amounts of antibiotics may not be able to eliminate the "dormant" cells, in particular persisters and Viable But Non Culturable cells (VBNCs). Surviving dormant cells play a critical role in the infection relapse. In addition of limiting the effect of antibacterial drugs, dormant cells may be responsible of chronic diseases. By contrast with drug resistance, persistence and activation of dormant cells is strongly associated with individual and environmental factors.

Very few options are currently available to eliminate dormant cells, because most treatments have been designed to kill active cells. One strategy to specifically target persisters is the use of drugs, e.g., antimicrobial peptides, that interact directly with the cell membrane, so that they are effective even on a metabolically inactive bacterium. Another option is to first reactivate the dormant cells, for example with saccharides, then use common antibacterials to eliminate the reactivated cells. The methods are however of limited applicability; and so far, no convenient therapeutic solution for persisters removal is available.

Thus, there is still a need in novel compounds which are able to restore or enhance the antibacterial activity of antibiotics, and more particularly to restore or enhance the antibacterial activity of existing antibiotics for the treatment of Gram-negative resistant strains, and/or which can give rise to an anti-persister effect of an antibiotic, while guaranteeing low toxicity towards humans and animals, and whose structure can be easily modified so as to adapt it to the type of bacteria.

As a result of intensive research, the present inventors have found that polyaminated fatty acids can enhance or restore the antibacterial activity of antibiotics against antibacterial drug-resistant bacteria. They have found that these polyaminated fatty acids can remarkably enhance the antibacterial activity of tetracycline- based antibacterial drugs against the resistant bacteria.

Therapeutic application

A first object of the present invention is the use of a polyaminated fatty acid compound responding to the following formula (I):

R¹-C( = O)-NH-(CR²R³)_m-[X-(CR⁴R⁵)n]_P-NR⁶R⁷ (I) in which:

- R¹ represents a linear aliphatic chain comprising at least 7 carbon atoms, where the linear aliphatic chain is a mono- or polyunsaturated aliphatic chain, or a saturated aliphatic chain; - R² and R³ represent, independently from each other, independently at each occurrence m, a hydrogen atom or a C1-C8 alkyl group; - R⁴ and R⁵ represent, independently from each other, independently at each occurrence n, independently at each occurrence p, a hydrogen atom or a C1-C8 alkyl group; - X represents, independently at each occurrence p, a -NR⁸- group or a divalent 5- to 7-membered heterocycloalkyl comprising at least one nitrogen atom; in which R⁸ represents a hydrogen atom, a C1-C6 alkyl group, or -(CH2)q- NH2 in which q represents an integer ranging from 1 to 5; - R⁶ and R⁷ represent, independently from each other, a hydrogen atom, a C1-C8 alkyl group, or R⁶ and R⁷ form together with the nitrogen atom to which they are attached a 5- to 7-membered heterocyclyl optionally substituted by one to three R⁹; where R⁹ represents -(CH2)u-NH2 in which u represents an integer ranging from 1 to 5; - m is an integer ranging from 2 to 10; - n represents, independently at each occurrence p, an integer ranging from 1 to 5; and - p is an integer ranging from 0 to 4, a pharmaceutically acceptable salt and/or solvate thereof, as an adjuvant to an antibacterial drug. Interestingly, the polyaminated fatty acid compounds as defined in the present invention are antibiotic enhancers and exhibit a strong effect of the level of antibiotics susceptibility against resistant bacteria strains, and more particularly against Gram-negative resistant bacteria strains. Additionally, such polyaminated fatty acid compounds do not display intrinsic antibacterial activity so that they do not trigger resistance mechanisms although they can greatly restore the antibacterial activity or enhance the antibacterial activity. They may act by membrane depolarization and/or integrity membrane disruption so that their mechanism of action may significantly reduce the development of resistance. In the present invention, the term “antibacterial drug” refers to a substance or a compound that kills bacteria or inhibits the growth of bacteria. The antibacterial drug is conventionnaly administrated in case of bacterial disease or infection.

In the present invention, the term "polyaminated fatty acid compound" includes the polyaminated fatty acid compound of formula (I), as well as a pharmaceutically acceptable salt and/or solvate thereof.

The aliphatic chain R¹

R¹ preferably comprises at least 9 carbon atoms, more preferably at least 11 carbon atoms, and even more preferably at least 13 carbon atoms.

R¹ preferably comprises at most 35 carbon atoms, more preferably at most 27 carbon atoms, and even more preferably at most 23 carbon atoms.

R¹ preferably comprises from 9 to 35 carbon atoms, more preferably from 11 to 27 carbon atoms, and even more preferably from 13 to 23 carbon atoms.

The linear aliphatic chain R¹ is a mono- or polyunsaturated aliphatic chain, or a saturated aliphatic chain, and preferably a mono- or polyunsaturated aliphatic chain. A mono- or polyunsaturated aliphatic chain leads to improved efficacy for enhancing antibacterial activity.

The mono- or polyunsaturated linear aliphatic chain R¹ may comprise from 1 to 6 unsaturations, preferably from 2 to 5 unsaturations, and more preferably from 2 to 4 unsaturations. The two latter ranges lead to lower toxicity towards mammals.

Each of the unsaturations may be of Z configuration (c/s configuration) or E configuration (trans configuration). In other words, the polyaminated fatty acid compound of the present invention may be in the form of a mixture of isomers or in the form of one isomer. Preferably the polyaminated fatty acid compound of the present invention is in the form of one isomer.

In the present invention, the term "aliphatic chain" means a hydrocarbonated chain and the term "aliphatic" is opposed to "aromatic".

In the present invention, the term "linear" means an unsubstituted or unbranched aliphatic chain.

The linear aliphatic chain R¹ is preferably a chain of a fatty acid selected from lauric acid, stearic acid, caproic acid, myristic acid, palmitic acid, arachidic acid, behenic acid, lignoceric acid, cerotic acid, montanic acid, melissic acid, tricosanoic acid, oleic acid, linoleic acid, lauroleic acid, myristoleic acid, palmitoleic acid, vaccenic acid, gadoleic acid ketoleic acid, erucic acid, selacholeic acid (nervonic acid), linolenic acid, stearidonic acid, eleostearic acid, arachidonic acid, cuplanodonic acid, elaidic acid, docosahexanoic acid, docosahexaenoic acid, docasapentaenoic acid, eicosapentaenoic acid and petroselinic acid. In one preferred embodiment, the linear aliphatic chain R¹ is preferably a chain of a fatty acid selected from lauric acid, stearic acid, palmitic acid, behenic acid, lignoceric acid, tricosanoic acid, oleic acid, linoleic acid, myristoleic acid, palmitoleic acid, selacholeic acid, arachidonic acid, and docasahexanoic acid. R² and R³ R² and R² represent, independently from each other, independently at each occurrence m, a hydrogen atom or a C1-C8 alkyl group. The C1-C8 alkyl group may be a linear or branched alkyl group, preferably a linear alkyl group or a branched alkyl group with branches comprising from 1 to 3 carbon atoms, and more preferably a linear alkyl group. In one preferred embodiment, R² and R³ represent, independently from each other, independently at each occurrence m, a hydrogen atom or a C1-C5 alkyl group, and more preferably a hydrogen atom or a C1-C3 alkyl group. Advantageously, at least one of R² and R³ is a hydrogen atom, and more advantageously R² and R³ are hydrogen atoms. m represents the occurrence of the -CR²R³- group. m ranges from 2 to 10, preferably from 2 to 6, and more preferably from 2 to 4. R² and R³ are selected independently at each occurrence m. In other words, it means that the couple (R², R³) (or the -CR²R³- group) may be identical or different for each occurrence m. Indeed, R² and R³ can take different meanings at each occurrence m. In one preferred embodiment, the couple (R², R³) (or the -CR²R³- group) is identical for each occurrence m. R⁴ and R⁵ R⁴ and R⁵ represent, independently from each other, independently at each occurrence n, independently at each occurrence p, a hydrogen atom or a Ci-Cs alkyl group.

The Ci-Cs alkyl group may be a linear or branched alkyl group, preferably a linear alkyl group or a branched alkyl group with branches comprising from 1 to 3 carbon atoms, and more preferably a linear alkyl group.

In one preferred embodiment, R⁴ and R⁵ represent, independently from each other, independently at each occurrence n, independently at each occurrence p, a hydrogen atom or a Ci-Cs alkyl group, and more preferably a hydrogen atom or a C1-C3 alkyl group.

Advantageously, at least one of R⁴ and R⁵ is a hydrogen atom, and more advantageously R⁴ and R⁵ are hydrogen atoms. n represents the occurrence of the -CR⁴R⁵- group, n ranges from 1 to 5, preferably from 2 to 5, and more preferably from 2 to 4.

R⁴ and R⁵ are selected independently at each occurrence n. In other words, it means that when n is greater than 1, the couple (R⁴, R⁵) (or the - CR⁴R⁵- group) may be identical or different for each occurrence n. Indeed, R⁴ and R⁵ can take different meanings at each occurrence n.

In one preferred embodiment, the couple (R⁴, R⁵) (or the -CR⁴R⁵- group) is identical for each occurrence n. p represents the occurrence of the [X-(CR⁴R⁵)_n] group. p ranges from 0 to 4, and preferably from 1 to 3, and more preferably from 2 to 3.

R⁴ and R⁵ are selected independently at each occurrence p. In other words, it means that when p is greater than 1, the couple (R⁴, R⁵) (or the - CR⁴R⁵- group) may be identical or different for each occurrence p. Indeed, R⁴ and R⁵ can take different meanings at each occurrence p.

Additionally, n represents, independently at each occurrence p, an integer ranging from 1 to 5. In other words, when p is greater than 1, n is able to take different values or meanings at each occurrence p.

Advantageously, at least one occurrence n is equal to 4.

X X represents, independently at each occurrence p, a -NR⁸- group or a divalent 5- to 7-membered heterocycloalkyl comprising at least one nitrogen atom; in which R⁸ represents a hydrogen atom, a C1-C6 alkyl group, or -(CH2)q- NH2 in which q represents an integer ranging from 1 to 5. X is selected independently at each occurrence p. In other word, it means that X may be identical or different for each occurrence p. Indeed, X can take different meanings at each occurrence p. In the present invention, the term “heterocycloalkyl” refers to a cyclic alkyl comprising from 2 to 7 carbon atoms and one or more heteroatoms, preferably selected from an oxygen atom, a nitrogen atom and mixture thereof. The divalent 5- to 7-membered heterocycloalkyl comprising at least one nitrogen atom (as group X) preferably comprises from 4 to 6 carbon atoms and at least one nitrogen atom as a heteroatom. In one preferred embodiment, the heterocycloalkyl is 5- or 6-membered, and more preferably 6-membered. The heterocycloalkyl preferably comprises one or two nitrogen atoms as heteroatoms. A hydrogen atom or a -(CH2)q-NH2 group is preferred for R⁸. The C1-C6 alkyl group may be a linear or branched alkyl group, preferably a linear alkyl group or a branched alkyl group with branches comprising from 1 to 3 carbon atoms, and more preferably a linear alkyl group. In one preferred embodiment, X represents, independently at each occurrence p, a -NR⁸- group or a divalent 5- to 7-membered heterocycloalkyl comprising at least one nitrogen atom; in which R⁸ represents a hydrogen atom, a C1-C3 alkyl group, or -(CH2)q-NH2 in which q represents an integer ranging from 1 to 3, and more preferably a -NR⁸- group in which R⁸ represents a hydrogen atom, a C1-C3 alkyl group, or -(CH2)q-NH2 in which q represents an integer ranging from 1 to 3. Examples of divalent 5- to 7-membered heterocycloalkyls comprising at least one nitrogen atom (as group X) are piperidine, and piperazine. R⁶ and R⁷ R⁶ and R⁷ represent, independently from each other, a hydrogen atom, a C1-C8 alkyl group, or R⁶ and R⁷ form together with the nitrogen atom to which they are attached a 5- to 7-membered heterocyclyl optionally substituted by one to three R⁹; where R⁹ represents -(CH2)u-NH2 in which u represents an integer ranging from 1 to 5. In the present invention, the term “heterocyclyl” refers to “heterocycloalkyl” as defined above and “heteroaryl” groups. In the present invention, the term “heteroaryl” refers to aromatic rings or aromatic ring systems comprising from 5 to 12 carbon atoms, preferably from 5 to 10 carbon atoms, having one or two rings which are fused together or linked covalently, wherein at least one ring is aromatic, and wherein one or more carbon atoms in one or more of these rings is replaced by heteroatom(s), preferably selected from an oxygen atom, a nitrogen atom, and mixture thereof. The C1-C8 alkyl group may be a linear or branched alkyl group, preferably a linear alkyl group or a branched alkyl group with branches comprising from 1 to 3 carbon atoms, and more preferably a linear alkyl group. In one preferred embodiment, R⁶ and R⁷ represent, independently from each other an hydrogen atom, a C1-C5 alkyl group, or R⁶ and R⁷ form together with the nitrogen atom to which they are attached a 5- to 7-membered heterocyclyl optionally substituted by one to three R⁹; where R⁹ represents - (CH2)u-NH2 in which u represents an integer ranging from 1 to 5, and more preferably a hydrogen atom, a C1-C3 alkyl group, or R⁶ and R⁷ form together with the nitrogen atom to which they are attached a 5- to 7-membered heterocyclyl optionally substituted by one to three R⁹; where R⁹ represents - (CH2)u-NH2 in which u represents an integer ranging from 1 to 5. u preferably represents an integer ranging from 2 to 4. The 5- to 7-membered heterocyclyl is preferably unsubstituted or substituted by one R⁹. The 5- to 7-membered heterocyclyl is preferably selected from piperazinyl and imidazolyl. Examples of 5- to 7-membered heterocyclyl optionally substituted by one to three R⁹ which are formed with R⁶, R⁷ and the nitrogen atom to which they are attached are the following ones:

Advantageously, at least one of R⁶ and R⁷ is a hydrogen atom, and more advantageously R⁶ and R⁷ are hydrogen atoms. -NH-(CR²R³)m-[X-(CR⁴R⁵)n]p-NR⁶R⁷ The group -NH-(CR²R³)^m-[X-(CR⁴R⁵)ⁿ]^p-NR⁶R⁷ is preferably selected from the following groups:

In one particularly preferred embodiment, the polyaminated fatty acid compound is selected from the following polyaminated fatty acid compounds: PAFA14

a pharmaceutically acceptable salt and/or solvate thereof.

Within the above-mentioned polyaminated fatty acid compound, the ones with polyunsaturated aliphatic chains as R.¹ group are particularly preferred.

The polyaminated fatty acid compound is used as an adjuvant to an antibacterial drug. As mentioned in the background art, an adjuvant is also called "resistance circuit breaker", "chemosensitizer" or "(antibiotic) potentiator". The antibacterial drug and the polyaminated fatty acid compound are administered in amounts that together are more effective to inhibit bacteria than administration of the same amount of the antibacterial drug without the polyaminated fatty acid compound.

Preferably, the polyaminated fatty acid compound may be defined as an adjuvant of an antibacterial drug if a potentiator effect or a restoration effect is observed when said polyaminated fatty acid compound is administrated at a concentration Ca (in pM), where Ca < MICa/4, and MICa represents the minimum inhibitory concentration (in pM) of said polyaminated fatty acid compound with respect to a given bacterial strain.

A potentiator or restoration effect is observed when a MIC ratio is greater than 1, where the MIC ratio = MIC of said antibacterial drug alone for said strain (in pM) I MIC of said antibacterial drug in the presence of said compound (in pM).

The adjuvant and the antibacterial drug administration can be performed simultaneously, separately, or sequentially.

In the use of the present invention, the antibacterial drug is preferably selected from tetracyclines and macrolides.

Tetracyclines are particularly preferred.

Examples of tetracyclines are tetracycline, doxycycline, minocycline, or tigecycline.

Examples of macrolides are erythromycin, clarithromycin, azithromycin, josamycin, roxithromycin, spiramycin, dirithromycin, or tylosin.

Pharmaceutically acceptable salts include acetate, adipate, aspartate, benzoate, besylate, bicarbonate/carbonate, bisulphate/sulphate, borate, camsylate, citrate, cyclamate, edisylate, esylate, formate, fumarate, gluceptate, gluconate, glucuronate, hexafluorophosphate, hibenzate, hydrochloride/chloride, hydrobrom ide/brom ide, hydroiodide/iodide, isethionate, lactate, malate, maleate, malonate, mesylate, methylsulphate, naphthylate, 2-napsylate, nicotinate, nitrate, orotate, oxalate, palmitate, pamoate, phosphate/hydrogen phosphate/dihydrogen phosphate, pyroglutamate, saccharate, stearate, succinate, tannate, tartrate, tosylate, trifluoroacetate, and xinafoate salts.

Pharmaceutically acceptable salts of compounds (I) of the invention may be prepared by reacting the compound (I) with the corresponding appropriate acid or by means of a suitable ion exchange column. All these reactions are typically carried out in solution. The salt may precipitate from solution and be collected by filtration or may be recovered by evaporation of the solvent. The degree of ionization in the salt may vary from completely ionized to almost nonionized.

"Solvate" refers to molecular complex comprising a compound (I) along with stoichiometric or sub-stoichiometric amounts of one or more molecules of one or more solvents. Typically, the solvent is a pharmaceutically acceptable solvent such as, for example, ethanol. The term "hydrate" refers to a solvate when the solvent is water (H2O). Solvates of compounds (I) include conventional solvates such as those formed during the last step of preparation of these compounds due to the presence of solvents.

The polyaminated fatty acid compound as defined in the first object of the present invention is particularly useful as an adjuvant to an antibacterial drug, for the treatment of bacterial diseases or infections, and in particular caused by Gram-negative bacteria.

Thus, the polyaminated fatty acid compound as defined in the first object of the present invention may be used in the treatment of bacterial diseases or infections, and in particular caused by Gram-negative bacteria.

The invention also relates to a polyaminated fatty acid compound as defined in the first object of the present invention, for medical use.

"Gram-negative bacteria" refers to bacteria that do not retain the crystal violet stain used in the Gram staining. Gram-negative bacteria are characterized by a bacterial cell wall composed of a thin layer of peptidoglycan in between an inner cytoplasmic cell membrane and a bacterial outer membrane.

The Gram-negative bacteria is preferably selected from Pseudomonas bacteria, Escherichia bacteria, Klebsiella bacteria, Acinetobacter bacteria, Enterobacter bacteria and Legionella bacteria, and more preferably selected from Pseudomonas bacteria and Escherichia bacteria.

In one preferred embodiment, the Pseudomonas bacteria is Pseudomonas aeruginosa.

In one preferred embodiment, the Escherichia bacteria is Escherichia coli.

In one preferred embodiment, the Klebsiella bacteria is Klebsiella pneumoniae.

In one preferred embodiment, the Acinetobacter bacteria is Acinetobacter baumannii.

The polyaminated fatty acid compound as defined in the first object of the present invention is also particularly useful as an adjuvant to an antibacterial drug, for killing or inhibiting the growth of persister cells.

The polyaminated fatty acid compound as defined in the first object of the present invention can be prepared by reaction of a natural fatty acid and a polyamine, in the presence of a coupling agent such as BOP, a base such as diisopropylethylamine, and in an organic solvent such as dichloromethane. The reaction is generally performed at room temperature. The scheme below illustrates the reaction.

P P

A second object of the present invention is a pharmaceutical composition comprising at least one polyaminated fatty acid compound as defined in the first object of the present invention.

Preferably, the pharmaceutical composition comprises at least one polyaminated fatty acid compound as defined in the first object of the present invention and at least one antibacterial drug.

Indeed, the combination of said polyaminated fatty acid compound as defined in the first object of the present invention and an antibacterial drug leads to a pharmaceutical composition having improved antibacterial activity, in particular against antibacterial drug-resistant bacteria and/or having anti- persister activity towards dormant cells. In one preferred embodiment, the pharmaceutical composition comprises from about 0.1 weight % to about 50 weight % of said polyaminated fatty acid compound, and more preferably from about 0.2 weight % to about 30 weight % of said polyaminated fatty acid compound, with respect to the total weight of the pharmaceutical composition.

The pharmaceutical composition preferably comprises a therapeutically effective amount of the antibacterial drug.

"Therapeutically effective amount" (in short "effective amount") refers to the amount of a therapeutic agent that is sufficient to achieve the desired therapeutic, prophylactic, or preventative effect in the subject in need thereof to which/whom it is administered, without causing significant negative or adverse side effects to said patient. A therapeutically effective amount may be administered prior to the onset of the disease, disorder, or condition, for a prophylactic or preventive action. Alternatively, or additionally, the therapeutically effective amount may be administered after initiation of the disease, disorder, or condition, for a therapeutic action.

In one preferred embodiment, the pharmaceutical composition comprises from about 50 weight % to about 99,9 weight % of said antibacterial drug, and more preferably from about 70 weight % to about 99,8 weight % of said antibacterial drug, with respect to the total weight of the pharmaceutical composition.

In the pharmaceutical composition, the weight ratio of polyaminated fatty acid compound/antibacterial drug ranges preferably from about 0.2 to about 2, and more preferably from about 0.5 to about 1.

The antibacterial drug is as defined in the first object of the present invention.

The pharmaceutical composition may further comprise a pharmaceutically acceptable carrier.

"Pharmaceutically acceptable" means that the ingredients of the pharmaceutical composition are compatible with each other and not deleterious to the patient to which/whom it is administered. "Pharmaceutically acceptable carrier" refers to an excipient that does not produce an adverse, allergic, or other untoward reaction when administered to an animal or a human. It includes all solvents, dispersion media, coatings, antifungal agents, isotonic and absorption delaying agents and the like. For human administration, preparations should meet sterility, pyrogenicity, general safety and purity standards as required by regulatory offices, such as, e.g., FDA Office or EMA.

Examples of pharmaceutically acceptable carriers include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins, such as human serum albumin, buffer substances such as phosphates, glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes, such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinyl pyrrolidone, cellulose-based substances (for example sodium carboxymethylcellulose), polyethylene glycol, polyacrylates, waxes, polyethylene- polyoxypropylene- block polymers, polyethylene glycol and wool fat.

A third object of the present invention is a pharmaceutical composition as defined in the second object of the present invention for use as a medicament or for medical use.

A fourth object of the present invention is a pharmaceutical composition as defined in the second object of the present invention for use in the treatment of bacterial diseases; in particular caused by Gram-negative bacteria.

The bacterial disease can be selected from a chronic infection, a relapsing infection, a recalcitrant infection, a persistent infection, a persister related- infection, a persister related-chronic infection, a persister related-relapsing infection, a persister related-recalcitrant infection, and a persister related- persistent infection.

A fifth object of the present invention is a pharmaceutical composition as defined in the second object of the present invention for use for killing or inhibiting the growth of persister cells.

A sixth object of the present invention is a kit comprising: - a pharmaceutical composition comprising a polyaminated fatty acid compound as defined in the first object of the present invention, and

- a separate pharmaceutical composition comprising at least one antibacterial drug.

The antibacterial drug is as defined in the first object of the present invention.

The present invention further relates to a method for treating a bacterial disease in a subject in need thereof, comprising administering to the subject a pharmaceutical composition as defined in the second object of the present invention.

The present invention further relates to a method for treating a chronic infection, a relapsing infection, a recalcitrant infection, a persistent infection, a persister related-infection, a persister related-chronic infection, a persister related-relapsing infection, a persister related-recalcitrant infection, or a persister related-persistent infection in a subject in need thereof, comprising administering to the subject a pharmaceutical composition as defined in the second object of the present invention.

The present invention further relates to a method for killing or inhibiting the growth of persister cells in a subject in need thereof, comprising administering to the subject a pharmaceutical composition as defined in the second object of the present invention.

The present invention further relates to the use of a pharmaceutical composition as defined in the second object of the present invention, for the manufacture of a medicament for the treatment of a bacterial disease in a subject in need thereof.

The present invention further relates to the use of a pharmaceutical composition as defined in the second object of the present invention, as described herein, for the manufacture of a medicament for the treatment of a chronic infection, a relapsing infection, a recalcitrant infection, a persistent infection, a persister related-infection, a persister related-chronic infection, a persister related-relapsing infection, a persister related-recalcitrant infection, or a persister related-persistent infection in a subject in need thereof. The present invention further relates to the use of a pharmaceutical composition as defined in the second object of the present invention, for the manufacture of a medicament for killing or inhibiting the growth of persister cells in a subject in need thereof.

The present invention also relates to the use of a pharmaceutical composition as defined in the second object of the present invention, for treating a bacterial disease in a subject in need thereof.

The present invention also relates to the use of a pharmaceutical composition as defined in the second object of the present invention, for treating a chronic infection, a relapsing infection, a recalcitrant infection, a persistent infection, a persister related-infection, a persister related-chronic infection, a persister related-relapsing infection, a persister related-recalcitrant infection, or a persister related-persistent infection in a subject in need thereof.

The present invention also relates to the use of a pharmaceutical composition as defined in the second object of the present invention, for killing or inhibiting the growth of persister cells in a subject in need thereof.

"Bacterial infection" ou "bacterial disease" refers to any undesired presence and/or growth of bacteria as pathogen in a subject. Such undesired presence of microorganism may have a negative effect on the host subject's health and well-being. While the term "bacterial infection" ou "bacterial disease" should not be taken as encompassing the normal growth and/or presence of microorganism which are normally present in the subject, for example in the digestive tract of the subject, it may encompass the pathological overgrowth of such microorganism. "Bacterial infection" ou "bacterial disease" is a pathologic condition or disorder caused by the growth and/or presence of bacteria as microorganism. Therapeutic agents for the treatment of "bacterial infection" ou "bacterial disease" are "antibacterial" agents or drugs.

"Chronic infection", "relapsing infection", "recalcitrant infection" and "persistent infection" refer to bacterial infection which resists to the host immune system and antibiotic treatments and is capable of reactivation into clinically significant disease with chronic symptoms.

In one embodiment, the bacterial disease is selected from cystic fibrosis, urinary tract infection, chronic otitis, and pneumonia. In one preferred embodiment, the bacterial disease is caused by Gramnegative bacteria.

"Subject" refers to an animal, typically a warm-blooded animal, preferably a mammal. The term "mammal" refers here to any mammal, including humans, domestic and farm animals, and zoo, sports, or pet animals, such as dogs, cats, cattle, horses, sheep, pigs, goats, rabbits, etc. Preferably, the mammal is a primate, more preferably a human.

"Human" refers to a male or female human subject at any stage of development, including neonate, infant, juvenile, adolescent, and adult.

In one embodiment, the subject is affected, preferably is diagnosed, with a bacterial disease. In one embodiment, the subject is at risk of developing an bacterial disease. Examples of risks factor include, but are not limited to, genetic predisposition, or familial history of bacterial diseases.

"Persisters" refers to any type of dormant variants of regular cells, in particular persisters and viable but non-culturable cells (VBNCs). Persisters are susceptible to cause an infectious disease. Persisters are typically bacterial, however fungal persister cells, and yeast persister cells are also encompassed in this definition. Persisters represent a small subpopulation of genetically identical, metabolically slow-growing cells which spontaneously enter a dormant, nondividing state and can survive to extremely high antibiotic doses. When a population is treated with an antibiotic, regular cells die, whereas persisters survive. To kill, antibiotics require active targets, which explains persisters tolerance. By contrast, resistance mechanisms prevent antibiotics from binding to their targets. Resistance is measured by observing the ability of cells to grow in the presence of antibiotic. For the most part, the molecular mechanisms leading to persistence are unknown. As used herein, "persister cell" refers to metabolic variants of wild type microbial cells that are phenotypically characterized by their slow growth rate, which is typically 30%, 25%, 20%, 15%, 10%, 5% or less of the growth rate of the wild-type counterpart. In some embodiments, the persister cells are dormant and have, for example, no detectable cell division in a 24-hour period. Further, persister cells typically form colonies that are approximately 30%, 25%, 20%, 15%, 10%, 5% or less of the size of the colonies formed by their wild-type counterparts.

"Persister-related infection" refers to any infection in which persister cells are implicated.

The present invention also relates to the non-therapeutic use of a composition comprising a polyaminated fatty acid compound as defined in the present invention and an antibacterial drug, as anti -infective agent, preferably as anti-persister agent, more preferably for the disinfection of a surface and/or the purification of a liquid.

In this embodiment, the polyaminated fatty acid compound is not used or applied to a human or an animal. As a result, the polyaminated fatty acid compound is applied to an object such as a medical device, for example a protheses, or to a surface of said object for disinfection of such object or surface. Alternatively, the polyaminated fatty acid compound is mixed with a liquid or a fluid for purification of such liquid or fluid.

In this embodiment, the polyaminated fatty acid compound is used in combination with an antibacterial drug. The antibacterial can be as defined in the present invention or any known antiseptic agent or conventionally used in such type of non-therapeutic application.

The present invention also relates to a polyaminated fatty acid compound responding to the following formula (I'):

R¹-C( = O)-NH-(CR²R³)m-[X-(CR⁴R⁵)n]_P-NR⁶R⁷ (I') in which:

- R¹ represents a linear aliphatic chain comprising at least 7 carbon atoms, where the linear aliphatic chain is a mono- or polyunsaturated aliphatic chain;

- R² and R³ represent, independently from each other, independently at each occurrence m, a hydrogen atom or a Ci-Cs alkyl group;

- R⁴ and R⁵ represent, independently from each other, independently at each occurrence n, independently at each occurrence p, a hydrogen atom or a Ci-Cs alkyl group; - X represents, independently at each occurrence p, a -NR⁸- group or a divalent 5- to 7-membered heterocycloalkyl comprising at least one nitrogen atom; in which R⁸ represents a hydrogen atom, a Ci-Ce alkyl group, or -(CH2)_q- NH2 in which q represents an integer ranging from 1 to 5; - R⁶ and R⁷ represent, independently from each other, a hydrogen atom, a Ci-Cs alkyl group, or R⁶ and R⁷ form together with the nitrogen atom to which they are attached a 5- to 7-membered heterocyclyl optionally substituted by one to three R⁹; where R⁹ represents -(CH2)u-NH2 in which u represents an integer ranging from 1 to 5; - m is an integer ranging from 2 to 10;

- n represents, independently at each occurrence p, an integer ranging from 1 to 5; and

- p is an integer ranging from 0 to 4, a pharmaceutically acceptable salt and/or solvate thereof, with the exclusion of the following compounds and pharmaceutically acceptable salts and/or solvates thereof:

In formula (I'), R², R³, R⁴, R⁵, R⁶, R⁷, m, n, and p are as defined in the first object of the present invention. The linear aliphatic chain comprising at least 7 carbon atoms, where the linear aliphatic chain is a mono- or polyunsaturated aliphatic chain, as group R¹, is as defined in the first object of the present invention.

More particularly, the compounds of formula (I') are selected from the following compounds (I'-a) as a seventh object of the present invention:

a pharmaceutically acceptable salt and/or solvate thereof.

The present invention is illustrated in more detail in the examples below, but it is not limited to said examples.

Examples

Materials

All solvents for synthesis were purified using standard procedures, and reagents for synthesis were of commercial grade. Methanol, ethyl acetate and dichloromethane were purchased from VWR and used without purification.

Column chromatography was carried out on Silica Macherey Nagel (70- 230 mesh). Nuclear magnetic resonance (NMR) spectra were recorded on a Bruker AC 300 instrument 400 MHz for ¹H, 100 MHz for ¹³C) (the usual abbreviations are used: s: singlet, d: doublet, t: triplet, q: quadruplet, m : multiplet). Tetramethylsilane was used as internal standard. All chemical shifts are reported in ppm. Mass spectroscopy analysis was performed by Spectropole (Analytical Laboratory, University of Aix-Marseille). The purity of the compounds was verified by analytical HPLC (C18 column, CH3CN :water:trifluoroacetic acid (TFA) eluent: 90: 10:0.025, v/v/v), 0.5-1 ml/min) with a photo diode array (PDA) detector covering 210-310 nm. All compounds exhibited purity greater than 95% as determined by HPLC-PDA at 214 and 254 nm. The chemical compounds synthesized as hydrochloride were solubilized in distilled water and 10 mM stock solutions were prepared.

The bacterial strains used in the examples below are the reference strains P. aeruginosa ATCC27853, E. coli ATCC25922, K. pneumoniae ATCC51296, S. aureus ATCC25923 and E. faecalis ATCC29212. The bacterial strains were previously stored in 15% (v/v) glycerol at -80°C for cryoprotection. One colony of the fresh culture of each strain was incubated in a culture tube containing 3 ml of Mueller-Hinton broth (MH2) at 37°C overnight with agitation. This suspension was used for inoculum preparation. The antibiotics used in the examples below are: doxycycline, erythromycin, polymyxin B purchased from Sigma. These antibiotics were dissolved in sterile distilled water or dimethyl sulfoxide (DMSO) to obtain the desired concentration. Example 1: preparation of various polyaminated fatty acids (I) as defined in the present invention 1.1 Preparation of PAFA1 In a bicol flask, 282 mg of oleic acid (1 mmol) is placed under stirring in 15 ml of dichloromethane (CH2Cl2) and 202 mg of spermine (1 mmol), 129 mg of diisopropylethylamine (1 mmol) as well as 442 mg of ((1H- Benzo[d][1,2,3]triazol-1-yl)oxy)tris(dimethylamino)phosphonium hexafluorophosphate (1 mmol), also known as BOP, are added. The mixture is left under stirring for 12 hours at room temperature and then concentrated under vacuum. Purification of the crude mixture is performed by silica gel chromatography using a methanol eluent and then a mixture of CH2Cl2/methanol/NH4OH (7/3/1) (v/v/v). The product is obtained as a viscous yellow oil with a yield of 42% (cis-isomer only), referenced as PAFA1. PAFA1 has the following chemical formula:

1H NMR (400 MHz) (MeOD) δ: 0.83 (t, J = 2.5 Hz, 3H), 1.10-1.62 (m, 22H), 1.69-2.15 (m, 17H), 2.67-2.96 (m, 10H), 3.12-3.29 (m, 3H), 5.27 (m, 2H), 7.53 (m, 1H). 1³C NMR (100 MHz) (MeOD) δ: 176.26, 130.88, 130.77, 50.25, 47.56, 37.94, 37.14, 33.08, 30.86, 30.64, 30.47, 30.38, 30.34, 30.28, 29.97, 28.17, 28.01, 27.09, 23.76, 14.55. C28H58N4O MS (ESI+) m/z = 467.463 (100%, [M + H]⁺). 1.2 Preparation of PAFA2 In a bicol flask, 282 mg of oleic acid (1 mmol) is placed under stirring in 15 ml of dichloromethane (CH2Cl2) and 131 mg of bis(3-aminopropyl)amine (1 mmol), 129 mg of diisopropylethylamine (1 mmol) as well as 442 mg of BOP (1 mmol) are added. The mixture is left under stirring for 12 hours at room temperature and then concentrated under vacuum. Purification of the crude mixture is performed by silica gel chromatography using a methanol eluent and then a mixture of CH2Cl2/methanol/NH4OH (7/3/1) (v/v/v). The product is obtained as a viscous yellow oil with a yield of 13% (cis-isomer only), referenced as PAFA2. PAFA2 has the following chemical formula:

1H NMR (400 MHz, MeOD) δ: 0.92 (t, J = 6.82 Hz, 3H), 1.33 (d, J = 12.46 Hz, 20H), 1.62 (m, 2H), 1.70 (h, J = 6.99 Hz, 4H), 2.06 (p, J = 5.49, 6.79 Hz, 3H), 2.19 (t, J = 7.51 Hz, 2H), 2.62 (m, 4H), 2.72 (t, J = 7.12 Hz, 2H), 3.24 (t, J = 6.82 Hz, 2H), 5.36 (t, J = 4.64 Hz, 2H). 1³C NMR (100 MHz) (MeOD) δ: 176.28, 130.89, 48.26, 47.85, 40.58, 38.05, 37.15, 33.21, 33.07, 30.85, 30.63, 30.46, 30.36, 30.33, 30.26, 30.23, 28.15, 27.10, 23.75, 14.50. C24H49N3O MS (ESI+) m/z = 396.392 (100%, [M + H]⁺). 1.3 Preparation of PAFA3 In a bicol flask, 256 mg of palmitic acid (1 mmol) is placed under stirring in 15 ml of dichloromethane (CH2Cl2) and 131 mg of bis(3-aminopropyl)amine (1 mmol), 129 mg of diisopropylethylamine (1 mmol) as well as 442 mg of BOP (1 mmol) are added. The mixture is left under stirring for 12 hours at room temperature and then concentrated under vacuum. Purification of the crude mixture is performed by silica gel chromatography using a methanol eluent and then a mixture of CH2Cl2/methanol/NH4OH (7/3/1) (v/v/v). The product is obtained as a viscous yellow oil with a yield of 13%, referenced as PAFA3. PAFA3 has the following chemical formula:

¹H NMR (400 MHz, MeOD) δ: 0.92 (t, J = 6.81 Hz, 3H), 1.31 (s, 24H), 1.62 (dt, J = 8.31, 14.76 Hz, 2H), 1.71 (dt, J = 6.76, 14.14 Hz, 4H), 2.19 (t, J = 7.49 Hz, 2H), 2.62 (m, 4H), 2.72 (t, J = 7.11 Hz, 2H), 3.24 (t, J = 6.81 Hz, 2H). 1³C NMR (100 MHz, MeOD) δ: 176.34, 48.26, 47.85, 40.58, 38.05, 37.16, 33.15, 33.09, 30.81, 30.78, 30.75, 30.67, 30.49, 30.47, 30.34, 30.23, 27.11, 23.75, 14.47. C22H47N3O MS (ESI+) m/z = 370.375 (100%, [M + H]⁺). 1.4 Preparation of PAFA4 In a bicol flask, 256 mg of palmitic acid (1 mmol) is placed under stirring in 15 ml of dichloromethane (CH2Cl2) and 202 mg of spermine (1 mmol), 129 mg of diisopropylethylamine (1 mmol) as well as 442 mg of BOP (1 mmol) are added. The mixture is left under stirring for 12 hours at room temperature and then concentrated under vacuum. Purification of the crude mixture is performed by silica gel chromatography using a methanol eluent and then a mixture of CH²Cl²/methanol/NH⁴OH (7/3/1) (v/v/v). The product is obtained as a viscous yellow oil with a yield of 51%, referenced as PAFA4. PAFA4 has the following chemical formula:

1H NMR (400 MHz, MeOD) δ: 0.87 (m, 4H), 1.25 (s, 32H), 1.62 (s, 4H), 1.72 (p, J = 6.40 Hz, 3H), 2.15 (m, 4H), 2.67 (s, 3H), 2.75 (t, J = 6.55 Hz, 3H), 3.33 (q, J = 5.93 Hz, 3H). 1³C NMR (100 MHz, MeOD) δ: 175.69, 49.74, 47.01, 37.44, 36.88, 32.43, 30.18, 30.16, 30.05, 29.88, 29.86, 29.82, 29.33, 27.59, 26.50, 23.15, 14.30. C26H56N4O MS (ESI+) m/z = 441.446 (100%, [M + H]⁺). 1.5 Preparation of PAFA5 In a bicol flask, 328 mg of docosahexanoic acid (1 mmol) is placed under stirring in 15 ml of dichloromethane (CH2Cl2) and 131 mg of bis(3- aminopropyl)amine (1 mmol), 129 mg of diisopropylethylamine (1 mmol) as well as 442 mg of BOP (1 mmol) are added. The mixture is left under stirring for 12 hours at room temperature and then concentrated under vacuum. Purification of the crude mixture is performed by silica gel chromatography using a methanol eluent and then a mixture of CH2Cl2/methanol/NH4OH (7/3/1) (v/v/v). The product is obtained as a viscous yellow oil with a yield of 68% (only one isomer with all the double bonds in cis-configuration), referenced as PAFA5. PAFA5 has the following chemical formula:

1H NMR (400 MHz, MeOD) δ: 0.99 (t, J = 7.54 Hz, 3H), 1.72 (m, 5H), 2.10 (p, J = 7.33 Hz, 3H), 2.24 (t, J = 7.38 Hz, 2H), 2.40 (q, J = 6.89 Hz, 2H), 2.62 (dt, J = 7.27, 10.40 Hz, 4H), 2.73 (t, J = 7.10 Hz, 2H), 2.87 (m, 11H), 3.23 (d, J = 6.81 Hz, 2H), 5.38 (m, 13H). 1³C NMR (100 MHz, MeOD) δ: 175.42, 132.81, 130.18, 129.47, 129.25, 129.20, 129.15, 129.10, 128.92, 128.18, 48.23, 47.82, 40.53, 38.10, 36.95, 32.91, 30.18, 26.57, 26.52, 26.44, 24.74, 21.51, 14.71. C28H47N3O MS (ESI+) m/z = 442.386 (100%, [M + H]⁺ _). 1.6 Preparation of PAFA6 In a bicol flask, 328 mg of docosahexanoic acid (1 mmol) is placed under stirring in 15 ml of dichloromethane (CH2Cl2) and 202 mg of spermine (1 mmol), 129 mg of diisopropylethylamine (1 mmol) as well as 442 mg of BOP (1 mmol) are added. The mixture is left under stirring for 12 hours at room temperature and then concentrated under vacuum. Purification of the crude mixture is performed by silica gel chromatography using a methanol eluent and then a mixture of CH2Cl2/methanol/NH4OH (7/3/1) (v/v/v). The product is obtained as a viscous yellow oil with a yield of 39% (only one isomer with all the double bonds in cis-configuration), referenced as PAFA6. PAFA6 has the following chemical formula:

¹H NMR (400 MHz, MeOD) δ: 0.72 (t, J = 2.5 Hz, 3H), 1.07-1.53 (m, 10H), 1.84-1.98 (m, 3H), 1.98-2.18 (m, 3H), 2.37-2.46 (m, 8H), 2.52-2.70 (m, 16H), 3.03 (m, 3H), 3.45 (s, 2H), 4.82 (s, 1H), 5.21-5.06 (m, 12H), 8.02 (m, 1H). 1³C NMR (100 MHz, MeOD) δ: 175.36, 132.79, 130.15, 129.46, 129.25, 129.18, 129.13, 129.09, 128.90, 128.16, 50.26, 47.58, 38.01, 36.93, 29.98, 28.02, 26.57, 26.52, 26.45, 24.72, 21.51, 14.76. C32H56N4O MS (ESI+) m/z = 513.455 (100%, [M + H]⁺). 1.7 Preparation of PAFA7 In a bicol flask, 280 mg of linoleic acid (1 mmol) is placed under stirring in 15 ml of dichloromethane (CH2Cl2) and 74 mg of 1,3-propanediamine (1 mmol), 129 mg of diisopropylethylamine (1 mmol) as well as 442 mg of BOP (1 mmol) are added. The mixture is left under stirring for 12 hours at room temperature and then concentrated under vacuum. Purification of the crude mixture is performed by silica gel chromatography using a methanol eluent and then a mixture of CH²Cl²/methanol/NH⁴OH (7/3/1) (v/v/v). The product is obtained as a viscous yellow oil with a yield of 71% as a mixture of isomers, referenced as PAFA7. PAFA7 has the following chemical formula:

1H NMR (400 MHz, MeOD) δ: 0.94 (t, J = 6.90 Hz, 4H), 1.36 (s, 17H), 1.63 (m, 3H), 1.69 (m, 2H), 2.09 (q, J = 6.59 Hz, 4H), 2.21 (m, 2H), 2.70 (t, J = 6.98 Hz, 2H), 2.80 (t, J = 6.30 Hz, 2H), 3.26 (t, J = 6.79 Hz, 2H), 5.37 (d, J = 44.91 Hz, 4H). 1³C NMR (100 MHz, MeOD) δ: 176.31, 130.93, 130.86, 129.10, 129.04, 39.52, 37.45, 37.12, 32.96, 32.66, 30.74, 30.47, 30.37, 30.32, 30.27, 28.18, 27.07, 26.55, 23.63, 14.51. C21H40N2O MS (ESI+) m/z = 337.562 (100%, [M + H]⁺). 1.8 Preparation of PAFA8 In a bicol flask, 280 mg of linoleic acid (1 mmol) is placed under stirring in 15 ml of dichloromethane (CH2Cl2) and 88 mg of putrescine (1 mmol), 129 mg of diisopropylethylamine (1 mmol) as well as 442 mg of BOP (1 mmol) are added. The mixture is left under stirring for 12 hours at room temperature and then concentrated under vacuum. Purification of the crude mixture is performed by silica gel chromatography using a methanol eluent and then a mixture of CH2Cl2/methanol/NH4OH (7/3/1) (v/v/v). The product is obtained as a viscous yellow oil with a yield of 63% (only one isomer with all the double bonds in cis- configuration), referenced as PAFA8. PAFA8 has the following chemical formula:

1H NMR (400 MHz, MeOD) δ: 0.91 (t, J = 6.87 Hz, 3H), 1.34 (s, 15H), 1.54 (p, J = 3.48 Hz, 4H), 1.61 (m, 3H), 2.07 (q, J = 6.61 Hz, 4H), 2.18 (t, J = 7.53 Hz, 2H), 2.73 (t, J = 6.63 Hz, 2H), 2.78 (t, J = 6.23 Hz, 2H), 3.18 (t, J = 6.37 Hz, 2H), 5.35 (d, J = 44.70 Hz, 4H). 1³C NMR (100 MHz, MeOD) δ: 176.28, 130.95, 130.87, 129.11, 129.04, 41.64, 39.94, 37.16, 32.66, 30.73, 30.47, 30.34, 30.32, 30.25, 29.65, 28.16, 27.72, 27.08, 26.54, 23.62, 14.45. C22H42N2O MS (ESI+) m/z = 351.328 (100%, [M + H]⁺). 1.8 Preparation of PAFA9 In a bicol flask, 280 mg of linoleic acid (1 mmol) is placed under stirring in 15 ml of dichloromethane (CH2Cl2) and 145 mg of 3,3-diamino(N-methyl dipropylamine) (1 mmol), 129 mg of diisopropylethylamine (1 mmol) as well as 442 mg of BOP (1 mmol) are added. The mixture is left under stirring for 12 hours at room temperature and then concentrated under vacuum. Purification of the crude mixture is performed by silica gel chromatography using a methanol eluent and then a mixture of CH2Cl2/methanol/NH4OH (7/3/1) (v/v/v). The product is obtained as a viscous yellow oil with a yield of 48% (only one isomer with all the double bonds in cis-configuration), referenced as PAFA9. PAFA9 has the following chemical formula:

1H NMR (400 MHz, MeOD) δ: 0.87 (t, J = 6.85 Hz, 3H), 1.29 (s, 15H), 1.57 (m, 2H), 1.76 (p, J = 6.84 Hz, 2H), 1.89 (p, J = 7.09 Hz, 2H), 2.02 (q, J = 6.62 Hz, 4H), 2.17 (m, 2H), 2.46 (s, 3H), 2.68 (m, 2H), 2.73 (t, J = 6.34 Hz, 2H), 2.78 (t, J = 7.18 Hz, 2H), 3.02 (t, J = 7.07 Hz, 2H), 3.20 (t, J = 6.74 Hz, 2H), 5.30 (d, J = 44.49 Hz, 4H). 1³C NMR (100 MHz, MeOD) δ: 176.69, 130.85, 130.80, 128.97, 128.94, 55.67, 41.09, 39.52, 37.64, 36.99, 32.53, 30.63, 30.35, 30.23, 30.22, 30.17, 28.08, 28.06, 26.89, 26.78, 26.45, 24.18, 23.51, 14.41. C25H49N3O MS (ESI+) m/z = 408.390 (100%, [M + H]⁺). 1.10 Preparation of PAFA10 In a bicol flask, 280 mg of linoleic acid (1 mmol) is placed under stirring in 15 ml of dichloromethane (CH2Cl2) and 188 mg of tris(3-aminopropyl)amine (1 mmol), 129 mg of diisopropylethylamine (1 mmol) as well as 442 mg of BOP (1 mmol) are added. The mixture is left under stirring for 12 hours at room temperature and then concentrated under vacuum. Purification of the crude mixture is performed by silica gel chromatography using a methanol eluent and then a mixture of CH2Cl2/methanol/NH4OH (7/3/1) (v/v/v). The product is obtained as a viscous yellow oil with a yield of 28% (only one isomer with all the double bonds in cis-configuration), referenced as PAFA10. PAFA10 has the following chemical formula:

1H NMR (400 MHz, MeOD) δ: 0.89 (t, J = 6.90 Hz, 3H), 1.32 (s, 16H), 1.64 (d, J = 56.06 Hz, 10H), 2.05 (q, J = 6.60 Hz, 4H), 2.16 (t, J = 7.52 Hz, 2H), 2.48 (dt, J = 7.34, 14.36 Hz, 6H), 2.75 (q, J = 6.85 Hz, 6H), 3.17 (t, J = 7.00 Hz, 2H), 5.33 (d, J = 44.88 Hz, 4H). 1³C NMR (100 MHz, MeOD) δ: 176.19, 130.95, 130.86, 129.12, 129.04, 52.78, 52.48, 40.70, 38.65, 37.18, 32.66, 30.74, 30.47, 30.37, 30.33, 30.27, 29.27, 28.16, 27.65, 27.10, 26.54, 23.62, 14.47. C27H54N4O MS (ESI+) m/z = 451.442 (100%, [M + H]⁺). 1.11 Preparation of PAFA11 In a bicol flask, 280 mg of linoleic acid (1 mmol) is placed under stirring in 15 ml of dichloromethane (CH2Cl2) and 131 mg of bis(3-aminopropyl)amine (1 mmol), 129 mg of diisopropylethylamine (1 mmol) as well as 442 mg of BOP (1 mmol) are added. The mixture is left under stirring for 12 hours at room temperature and then concentrated under vacuum. Purification of the crude mixture is performed by silica gel chromatography using a methanol eluent and then a mixture of CH2Cl2/methanol/NH4OH (7/3/1) (v/v/v). The product is obtained as a viscous yellow oil with a yield of 52% (only one isomer with all the double bonds in cis-configuration), referenced as PAFA11. PAFA11 has the following chemical formula:

1H NMR (400 MHz, MeOD) δ: 0.91 (m, 3H), 1.35 (m, 15H), 1.62 (q, J = 7.43 Hz, 3H), 1.73 (dp, J = 7.06, 13.90 Hz, 4H), 2.07 (dt, J = 6.19, 8.38 Hz, 4H), 2.19 (t, J = 7.50 Hz, 2H), 2.64 (t, J = 7.13 Hz, 2H), 2.70 (t, J = 7.11 Hz, 2H), 2.78 (t, J = 6.17 Hz, 2H), 2.84 (t, J = 7.07 Hz, 2H), 3.23 (t, J = 6.79 Hz, 2H), 5.34 (m, 4H). 1³C NMR (100 MHz, MeOD) δ: 176.45, 130.95, 130.86, 129.12, 129.04, 48.15, 47.56, 40.29, 37.85, 37.13, 32.66, 30.76, 30.73, 30.47, 30.35, 30.32, 30.26, 30.01, 28.16, 27.09, 26.53, 23.62, 14.45. C24H47N3O MS (ESI+) m/z = 394.378 (100%, [M + H]⁺). 1.12 Preparation of PAFA12 In a bicol flask, 280 mg of linoleic acid (1 mmol) is placed under stirring in 15 ml of dichloromethane (CH2Cl2) and 146 mg of triethylenetetramine (1 mmol), 129 mg of diisopropylethylamine (1 mmol) as well as 442 mg of BOP (1 mmol) are added. The mixture is left under stirring for 12 hours at room temperature and then concentrated under vacuum. Purification of the crude mixture is performed by silica gel chromatography using a methanol eluent and then a mixture of CH2Cl2/methanol/NH4OH (7/3/1) (v/v/v). The product is obtained as a viscous yellow oil with a yield of 47% (only one isomer with all the double bonds in cis-configuration), referenced as PAFA12. PAFA12 has the following chemical formula:

1H NMR (400 MHz, MeOD) δ: 0.93 (t, J = 6.87 Hz, 3H), 1.35 (s, 16H), 1.62 (m, 2H), 2.08 (q, J = 6.60 Hz, 4H), 2.21 (t, J = 7.54 Hz, 2H), 2.74 (d, J = 13.16 Hz, 12H), 3.33 (d, J = 12.75 Hz, 4H), 5.36 (d, J = 45.03 Hz, 4H). 1³C NMR (100 MHz, MeOD) δ: 176.61, 130.95, 130.87, 129.11, 129.04, 51.69, 49.34, 41.47, 39.86, 37.15, 32.64, 30.71, 30.45, 30.33, 30.31, 30.24, 28.15, 26.97, 26.52, 23.61, 14.44. C24H48N4O MS (ESI+) m/z = 409.386 (100%, [M + H]⁺). 1.13 Preparation of PAFA13 In a bicol flask, 280 mg of linoleic acid (1 mmol) is placed under stirring in 15 ml of dichloromethane (CH2Cl2) and 188 mg of N,N’-bis(3- aminopropyl)1,3-propanediamine (1 mmol), 129 mg of diisopropylethylamine (1 mmol) as well as 442 mg of BOP (1 mmol) are added. The mixture is left under stirring for 12 hours at room temperature and then concentrated under vacuum. Purification of the crude mixture is performed by silica gel chromatography using a methanol eluent and then a mixture of CH2Cl2/methanol/NH4OH (7/3/1) (v/v/v). The product is obtained as a viscous yellow oil with a yield of 35% (only one isomer with all the double bonds in cis- configuration), referenced as PAFA13. PAFA13 has the following chemical formula:

1³C NMR (100 MHz, D2O) δ: 176.78, 130.79, 130.64, 128.83, 128.69, 45.67, 45.55, 37.52, 36.93, 32.35, 30.66, 30.22, 28.14, 27.97, 26.80, 26.69, 26.44, 24.70, 23.83, 23.62, 23.42, 14.77. C27H54N4O MS (ESI+) m/z = 451.453 (100%, [M + H]⁺). 1.14 Preparation of PAFA14 In a bicol flask, 280 mg of linoleic acid (1 mmol) is placed under stirring in 15 ml of dichloromethane (CH2Cl2) and 202 mg of spermine (1 mmol), 129 mg of diisopropylethylamine (1 mmol) as well as 442 mg of BOP (1 mmol) are added. The mixture is left under stirring for 12 hours at room temperature and then concentrated under vacuum. Purification of the crude mixture is performed by silica gel chromatography using a methanol eluent and then a mixture of CH2Cl2/methanol/NH4OH (7/3/1) (v/v/v). The product is obtained as a viscous yellow oil with a yield of 33% (only one isomer with all the double bonds in cis- configuration), referenced as PAFA14. PAFA14 has the following chemical formula:

¹H NMR (400 MHz, MeOD) δ: 0.92 (t, J = 8.0 Hz, 3H), 1.27-1.35 (m, 14H), 1.54-1.73 (m, 13H), 2.05-2.09 (m, 4H), 2.17-2.21 (t, J = 8.0 Hz, 2H), 2.31-2.36 (m, 3H), 2.60-2.63 (m, 6H), 2.78-2.80 (t, J = 8.0 Hz, 4H), 3.22- 3.25 (m, 2H), 3.32-3.40 (m, 3H), 5.30-5.4 (m, 3H) 1³C NMR (100 MHz, MeOD) δ: 176.36, 130.96, 130.87, 129.13, 129.05, 69.79, 56.12, 56.08, 53.67, 50.39, 47.71, 45.52, 37.99, 37.14, 32.66, 30.74, 30.48, 30.36, 30.31, 30.27, 30.08, 28.33, 28.17, 27.09, 26.89, 26.55, 25.60, 25.40, 23.63, 14.46. C28H56N4O MS (ESI+) m/z = 465.465 (100%, [M + H]⁺). Example 2: intrinsic antibacterial activity of polyaminated fatty acids (I) and their toxicity towards eucaryotic cells The polyaminated fatty acid compounds obtained by the reductive amination reaction described in example 1 above were all prepared as hydrochloride salts for biological testing. The antibacterial activity of said polyaminated fatty acid compounds was measured using a standard microdilution test based on Clinical and Laboratory Standards Institute (CLSI) guidelines. This method was slightly modified by increasing the assay volumes to 200 μl so as to improve reproducibility. 2.1 preparation of a preculture A negative control which corresponds to 2 ml of sterile culture medium and a positive control which corresponds to a mixture of 1980 µl of culture medium and 20 µl of bacterial suspension from a thawed biological strain (biological strains are stored at -80°C in glycerol) were prepared. The tubes were incubated in an incubator shaker “Infors” at 37°C for 24 hours at 100 round per minute (rpm). Germs were handled under a hood in the laboratory and before any manipulation a UV cycle was programmed and only sterile material was used. The polyaminated fatty acid compounds to be tested were prepared in water at a concentration of 10 mM. 2.2 preparation of a 96-well microplate and measurement of intrinsic antibacterial activity The required volume of the microbial suspension to be inoculated was calculated for an optical density (OD) measured corresponding to a value equal to 0.01 in each well by using a spectrophotometer at 600 nm. In the microplate, the first row corresponded to the negative control (200 µl of sterile culture medium in each well), the second row to the positive control (seeded culture medium), the third row was loaded twice with bacterial suspension and with 8 µl of a given polyaminated fatty acid compound in each well. Subsequently, a half-fold cascade dilution was performed from this line. The first column was used as an inhibition control. A sterile filter was then placed on the microplate allowing the passage of gases but not contaminants. The microplate was incubated at 37°C in a humid atmosphere for 24 hours. After 24 hours of incubation, an optical density measurement was performed by taking 100 µl of the bacterial suspension diluted in 900 µl of sterile culture medium. The medium used was Mueller-Hinton medium (MH) for bacteria. All tests were performed in duplicate. 2.3 Toxicity of polyaminated fatty acid compounds (I) on mammalian cells The WST1 assay was used to measure the cytotoxic activity of the polyaminated fatty acid compounds. It is a colorimetric assay that measures viability and cell proliferation rate. It is based on the cleavage of colorless tetrazolium salts WST-1 (4-[3-(4-iodophenyl)-2-(4-nitrophenyl)-2H-5- tetrazolio]-1,3-benzene disulfonate) by mitochondrial dehydrogenases into yellow formazan derivative, quantifiable by spectrophotometry at 420-480 nm. The WST1 assay was performed on Chinese hamster ovary cells. CHO- K1 cells (ATCC, USA) were maintained in culture in “Mac Coy's 5A” medium supplemented with 10% fetal calf serum, 2 mM L-glutamine and streptomycin penicillin mixture (100 U/ml: 10 µg/ml). Incubation is carried out at 37°C under CO2 enriched atmosphere (5% by volume) and subcultured every two days. Cells are transferred to 96-well plates (25,000 cells/ml) in complete “Mac Coy's 5A medium”, and maintained for 24 h at 37°C under a humid CO2- enriched atmosphere (5% by volume). Increasing concentrations of given polyaminated fatty acid compounds are added to the wells in duplicate assays and 8 growth controls containing cells in medium alone are included in each assay run. After 24 hours at 37°C (5% CO2), the culture medium is removed, the cells are rinsed in phosphate buffer (PBS) and 50 µL of PBS containing 10% WST1 reagent is added to each well. After 20 minutes of incubation at 37°C, the results are read by spectrophotometry at 450 nm. The results are expressed as dose-response relationships, modeled by a non-linear regression analysis using TableCurve software. The 50% Inhibitory Concentration (IC50) represents the concentration of polyaminated fatty acid compound capable of reducing cell viability by 50%. Table 1 below reports the intrinsic antibacterial activity of some polymaminated fatty acids prepared in example 1 (MIC in µM) as well as their toxicity towards eucaryotic cells (IC50 in µM).

ND: not determined TABLE 1 Table 1 shows that the polyaminated fatty acid compounds as defined in the present invention do not exhibit intrinsic antibacterial activity on one or more of the following bacterial strains: P. aeruginosa ATCC27853, E. faecalis ATCC29212, S. aureus ATCC25923, E. coli ATCC25922. Additionally, it is demonstrated that such polyaminated fatty acid compounds (I) do not exhibit toxicity towards mammalian cells. Example 3: use of polyaminated fatty acid compounds (I) as defined in the present invention in combination with an antibacterial drug 100 μl of a liquid culture medium is deposited in each well of a 96-well microplate, and then inoculated with the bacterial suspension of example 2.1 prepared for the positive control. The volume needed to inoculate is calculated for an OD of 0.01 which corresponds to approximately 5,106 bacteria in each well. In this plate, the first row corresponds to a negative control (200 μl of sterile culture medium in each well), the second row to a positive control (100 μl of sterile culture medium with 100 μl of the bacterial suspension), the third row contains 192 μl of culture medium and 8 μl of polyaminated fatty acid compound to be tested in each well. Subsequently, a cascade dilution is performed from this line. Next, 3-8 µl of a doxycycline solution (1 mg dissolved in 20 ml) is added to each well of the lines to obtain a final antibiotic concentration of 2 µg/ml. Then, 92 µl of bacterial suspension is added to lines 3 to 8. The MIC with a concentration of doxycycline of 2 µg/ml in the presence of X µg/ml of polyaminated fatty acid compound is determined after 24 hours of incubation at 37°C in a humid atmosphere. After 24 hours of incubation at 37°C, 40 μl of nitro tetrazolium iodide is added to each well allowing the presence of live bacteria to be revealed by staining the medium pink. The table 2 below reports the antibacterial activity (MIC in µM) of a combination of some polyaminated fatty acids prepared in example 1 with two antibacterial drugs doxycycline and erythromycin. On the Gram-negative strain of P. aeruginosa (ATCC27853), doxycycline has a MIC of 32 µg/ml. On the Gram-negative strain of E. coli (ATCC28922), erythromycin has a MIC of 50 µg/ml.

ND: not determined TABLE 2 Indeed, table 2 shows the ability of polyaminated fatty acids (I) prepared in example 1 to potentiate doxycycline and/or erythromycin used at a concentration of 2 µg/ml against bacterial strains of P. aeruginosa ATCCC27853 and E. coli ATCC25922, which are known to be gram negative bacterial resistant strains. Example 4: use of polyaminated fatty acid compounds (I) as defined in the present invention as potentiators of known antibiotics 100 μl of a liquid culture medium is deposited in each well of a 96-well microplate, and then inoculated with the bacterial suspension of example 2.1 prepared for the positive control. The volume needed to inoculate is calculated for an OD of 0.01 which corresponds to approximately 5,106 bacteria in each well. In this plate, the first row corresponds to a negative control (200 μl of sterile culture medium in each well), the second row to a positive control (100 μl of sterile culture medium with 100 μl of the bacterial suspension), the third row contains 192 μl of culture medium and 8 μl of an antibiotic solution (10 mg/ml) to be tested in each well. Subsequently, a cascade dilution is performed from this line. Next, 10 µl of a fatty acid solution (10 µM final concentration) is added to each well of the lines. Then, 90 µl of bacterial suspension is added to lines 3 to 8. The MIC of the antibiotic tested is determined after 24 hours of incubation at 37°C in a humid atmosphere. After 24 hours of incubation at 37°C, 40 μl of nitro tetrazolium iodide is added to each well allowing the presence of live bacteria to be revealed by staining the medium pink. The table 3 below reports the antibacterial activity (MIC in µg/mL) of a combination of some polyaminated fatty acids prepared in example 1 with various antibacterial drugs: doxycycline (DOX), tetracycline (TET), oxytetracycline (OXY) and minocycline (MINO), against various bacterial strains of P. aeruginosa (PA01, PA0509, and PA263), and of E. coli (AG-100 and AG- 100A).

TABLE 3

Table 3 shows a significant reduction in MIC (at least 4-fold reduction) thanks to the combination of a polyaminated fatty acid compound (I) and an antib acterial drug against gram-negative bacterial strains. This demonstrated the potentiator effect of the polyaminated fatty acid compounds (I) as defined in the present invention.

Example 5: preparation of other polvaminated fatty acid compounds (I) as defined in the present invention and use as potentiators of known antibiotics

Some other polyaminated fatty acid compounds responding to formula (I) PAFA15-27 have been prepared according to the same procedures as described for compounds PAFA1-14.

The structures of polyaminated fatty acid compounds PAFA15-27 are respectively reported below as well as their corresponding NMR and mass characteristics.

PAFA15 has the following chemical formula:

1H NMR (400 MHz, MeOD) δ 5.36 (m, 13H), 4.87 (s, 4H), 3.23 (t, J = 6.77 Hz, 2H), 2.85 (dt, J = 5.96, 11.87 Hz, 11H), 2.81 (d, J = 4.81 Hz, 2H), 2.72 (d, J = 17.52 Hz, 4H), 2.64 (m, 2H), 2.38 (m, 2H), 2.23 (t, J = 7.22 Hz, 2H), 2.07 (qd, J = 1.34, 7.41 Hz, 2H), 1.71 (m, 4H), 0.97 (t, J = 7.55 Hz, 3H). 1³C NMR (101 MHz, MeOD) δ 175.52, 132.81, 130.19, 129.47, 129.25, 129.21, 129.18, 129.14, 129.10, 128.92, 128.18, 49.29, 48.17, 47.63, 40.30, 37.98, 36.95, 31.15, 30.10, 26.58, 26.56, 26.53, 26.44, 24.74, 21.51, 14.69. C30H52N4O MS (ESI+) m/z = 485.4172 (100%, [M + H]⁺). PAFA16 has the following chemical formula:

1H NMR (400 MHz, MeOD) δ: 3.24 (t, J = 6.79 Hz, 2H), 2.82 (q, J = 7.40 Hz, 2H), 2.67 (dt, J = 7.14, 23.60 Hz, 4H), 2.19 (t, J = 7.47 Hz, 2H), 1.72 (dq, J = 6.99, 11.81 Hz, 4H), 1.61 (t, J = 7.29 Hz, 2H), 1.31 (d, J = 10.00 Hz, 18H), 0.91 (t, J = 6.76 Hz, 3H). 1³C NMR (101 MHz, MeOD) δ: 176.50, 69.85, 53.78, 48.16, 47.58, 45.51, 40.31, 38.65, 37.87, 37.15, 33.06, 30.97, 30.73, 30.64, 30.46, 30.33, 30.30, 30.02, 27.09, 26.88, 23.73, 14.45. C18H39N3O MS (ESI+) m/z = 314.3127 (100%, [M + H]⁺). PAFA17 has the following chemical formula:

1H NMR (400 MHz, MeOD) δ: 3.25 (t, J = 6.78 Hz, 3H), 2.78 (dt, J = 7.11, 23.17 Hz, 2H), 2.67 (m, 6H), 2.20 (t, J = 7.49 Hz, 3H), 1.75 (h, J = 6.78 Hz, 4H), 1.62 (dq, J = 3.55, 7.03 Hz, 7H), 1.33 (d, J = 10.55 Hz, 21H), 0.92 (m, 4H). ¹³C NMR (101 MHz, MeOD) δ: 176.43, 50.12, 50.06, 47.98, 47.47, 40.35, 37.89, 37.14, 33.07, 31.37, 30.75, 30.66, 30.47, 30.34, 29.89, 29.84, 28.09, 27.87, 27.78, 27.10, 25.32, 23.74, 14.49. C22H48N4O MS (ESI+) m/z = 385.3845 (100%, [M + H]⁺). PAFA18 has the following chemical formula:

1H NMR (400 MHz, MeOD) δ: 5.34 (dh, J = 4.95, 11.28 Hz, 6H), 3.45 (d, J = 6.48 Hz, 2H), 3.25 (t, J = 6.80 Hz, 3H), 2.80 (m, 13H), 2.12 (dq, J = 7.20, 46.41 Hz, 7H), 1.67 (m, 12H), 1.32 (s, 10H), 0.97 (m, 2H). 1³C NMR (101 MHz, MeOD) δ: 176.73, 132.72, 131.05, 129.20, 129.18, 128.85, 128.22, 69.54, 53.41, 49.48, 46.88, 45.35, 37.41, 37.05, 30.71, 30.35, 30.32, 30.25, 28.82, 28.17, 27.02, 26.86, 26.52, 26.51, 26.41, 24.96, 21.49, 14.70. C²⁸H⁵⁴N⁴O MS (ESI+) m/z = 463.4329 (100%, [M + H]⁺). PAFA19 has the following chemical formula:

1H NMR (400 MHz, MeOD) δ: 5.36 (m, 7H), 3.40 (d, J = 28.64 Hz, 2H), 3.25 (t, J = 6.76 Hz, 2H), 2.78 (m, 12H), 2.16 (m, 8H), 1.77 (ddt, J = 7.01, 9.25, 14.07 Hz, 3H), 1.63 (m, 7H), 1.36 (m, 9H), 0.91 (t, J = 6.73 Hz, 3H). 1³C NMR (101 MHz, MeOD) δ: 176.43, 131.15, 130.63, 129.26, 129.17, 129.05, 128.73, 74.26, 69.53, 55.77, 53.47, 49.85, 47.67, 47.22, 45.31, 40.05, 37.74, 36.98, 32.58, 30.38, 30.17, 29.42, 28.13, 27.93, 27.49, 26.68, 25.03, 23.57, 14.50. C28H54N4O MS (ESI+) m/z = 463.4246 (100%, [M + H]⁺). PAFA20 has the following chemical formula:

1H NMR (400 MHz, MeOD) δ: 3.23 (t, J = 6.80 Hz, 4H), 2.65 (m, 8H), 2.19 (t, J = 7.47 Hz, 3H), 1.63 (m, 11H), 1.32 (m, 20H), 0.91 (m, 4H). 1³C NMR (101 MHz, MeOD) δ: 176.41, 50.30, 50.26, 48.09, 47.61, 40.47, 37.97, 37.95, 37.15, 33.06, 32.14, 30.70, 30.66, 30.46, 30.33, 30.05, 30.03, 28.07, 28.05, 27.96, 27.11, 23.73, 14.47. C21H46N4O MS (ESI+) m/z = 371.3754 (100%, [M + H]⁺). PAFA21 has the following chemical formula:

1³C NMR (101 MHz, MeOD) δ: 176.41, 48.21, 47.74, 40.47, 37.98, 37.15, 33.06, 32.28, 30.70, 30.65, 30.45, 30.32, 30.14, 27.10, 23.73, 14.45. 1H NMR (400 MHz, MeOD) δ: 3.24 (t, J = 6.82 Hz, 2H), 2.76 (t, J = 7.11 Hz, 2H), 2.64 (m, 4H), 2.19 (t, J = 7.50 Hz, 2H), 1.71 (p, J = 7.32 Hz, 4H), 1.61 (m, 3H), 1.32 (m, 16H), 0.90 (m, 3H). C17H37N3O MS (ESI+) m/z = 300.2934 (100%, [M + H]⁺). PAFA22 has the following chemical formula:

1H NMR (400 MHz, MeOD) δ: 5.38 (m, 5H), 3.38 (s, 5H), 3.24 (dt, J = 6.86, 12.02 Hz, 2H), 2.83 (m, 5H), 2.67 (dt, J = 7.20, 18.26 Hz, 3H), 2.35 (m, 1H), 2.16 (m, 6H), 1.70 (ddq, J = 7.37, 15.69, 34.18 Hz, 6H), 1.36 (m, 8H), 0.93 (t, J = 6.73 Hz, 3H). ¹³C NMR (101 MHz, MeOD) δ: 176.37, 176.18, 131.16, 130.64, 130.62, 129.27, 129.19, 129.05, 128.74, 74.26, 69.71, 53.72, 53.59, 49.85, 48.08, 47.58, 45.39, 40.29, 38.66, 37.93, 37.03, 37.01, 32.59, 31.44, 30.38, 30.28, 29.96, 28.12, 27.92, 27.32, 26.79, 26.72, 26.51, 23.57, 14.45. C²⁴H⁴⁵N³O MS (ESI+) m/z = 392.3596 (100%, [M + H]⁺). PAFA23 has the following chemical formula:

1H NMR (400 MHz, MeOD) δ: 5.33 (hept, J = 6.40, 7.12 Hz, 14H), 3.24 (q, J = 3.35, 4.86 Hz, 3H), 2.80 (dq, J = 5.41, 5.87, 26.52 Hz, 16H), 2.58 (m, 7H), 2.36 (m, 3H), 2.22 (m, 3H), 2.06 (p, J = 7.45 Hz, 3H), 1.42 (d, J = 4.14 Hz, 1H), 0.95 (t, J = 7.54 Hz, 4H). 1³C NMR (101 MHz, MeOD) δ: 175.56, 132.80, 130.14, 129.45, 129.27, 129.20, 129.18, 129.13, 129.08, 128.90, 128.16, 56.07, 55.17, 39.63, 38.53, 36.93, 28.79, 26.59, 26.56, 26.55, 26.51, 26.45, 26.43, 24.63, 21.50, 14.74, 14.70. C31H54N4O MS (ESI+) m/z = 499.4331 (100%, [M + H]⁺). PAFA24 has the following chemical formula:

¹H NMR (400 MHz, MeOD) δ: 5.34 (ttd, J = 1.41, 5.70, 6.16, 11.65 Hz, 6H), 3.18 (t, J = 7.03 Hz, 2H), 2.81 (dt, J = 6.50, 10.02 Hz, 8H), 2.49 (dt, J = 7.41, 22.06 Hz, 6H), 2.10 (m, 7H), 1.66 (m, 9H), 1.33 (m, 11H), 0.96 (t, J = 7.53 Hz, 3H). 1³C NMR (101 MHz, MeOD) δ: 176.25, 132.73, 131.06, 130.94, 130.85, 129.20, 129.11, 129.03, 128.86, 128.23, 125.14, 124.98, 52.67, 52.34, 40.44, 38.55, 37.18, 32.65, 30.71, 30.47, 30.36, 30.33, 30.26, 28.17, 28.08, 27.70, 27.09, 26.85, 26.54, 26.52, 26.40, 23.62, 21.49, 14.68, 14.45. C27H52N4O MS (ESI+) m/z = 449.4175 (100%, [M + H]⁺). PAFA25 has the following chemical formula:

1H NMR (400 MHz, MeOD) δ: 5.35 (m, 6H), 3.25 (m, 4H), 2.77 (ddt, J = 7.17, 31.57, 64.30 Hz, 9H), 2.12 (m, 7H), 1.71 (m, 7H), 1.35 (p, J = 4.87 Hz, 10H), 0.98 (t, J = 7.55 Hz, 3H). 1³C NMR (101 MHz, MeOD) δ: 176.53, 132.73, 131.05, 130.94, 130.85, 129.20, 129.03, 128.87, 128.23, 48.09, 47.43, 40.14, 37.77, 37.13, 32.66, 30.71, 30.47, 30.34, 30.32, 30.25, 29.93, 29.74, 28.16, 27.08, 26.52, 26.40, 23.63, 21.49, 14.66, 14.44. C22H48N4O MS (ESI+) m/z = 385.3845 (100%, [M + H]⁺). PAFA26 has the following chemical formula:

1H NMR (400 MHz, MeOD) δ: 5.38 (m, 14H), 3.23 (t, J = 6.83 Hz, 3H), 2.86 (dd, J = 6.64, 12.11 Hz, 12H), 2.66 (m, 8H), 2.40 (m, 3H), 2.24 (m, 3H), 2.10 (m, 3H), 1.71 (dq, J = 7.41, 14.31 Hz, 6H), 0.99 (t, J = 7.55 Hz, 3H). ¹³C NMR (101 MHz, MeOD) δ: 175.46, 132.81, 130.18, 129.46, 129.25, 129.24, 129.21, 129.19, 129.14, 129.09, 128.96, 128.91, 128.17, 48.74, 48.72, 48.21, 47.79, 40.51, 38.10, 36.96, 32.60, 30.16, 30.13, 29.96, 29.87, 26.57, 26.52, 26.45, 24.75, 21.51, 14.72, 14.70. C³¹H⁵⁴N⁴O MS (ESI+) m/z = 499.4331 (100%, [M + H]⁺). PAFA27 has the following chemical formula:

1H NMR (400 MHz, MeOD) δ: 3.15 (dt, J = 6.63, 26.81 Hz, 3H), 2.65 (m, 10H), 2.14 (t, J = 7.51 Hz, 2H), 1.61 (m, 11H), 1.27 (dd, J = 4.40, 8.38 Hz, 14H), 0.86 (m, 3H). 1³C NMR (101 MHz, MeOD) δ: 176.35, 166.02, 50.23, 50.21, 49.88, 48.05, 47.58, 47.50, 46.59, 40.40, 39.33, 37.94, 37.14, 33.04, 31.92, 30.62, 30.47, 30.41, 30.33, 30.18, 29.97, 29.88, 27.97, 27.89, 27.61, 27.10, 26.86, 23.73, 14.49. C20H44N4O MS (ESI+) m/z = 357.3549 (100%, [M + H]⁺). They were all tested i combination of 2 µg/ml of doxycycline. Figure 1 reports the antibacterial activity (MIC in µg/mL) of doxycycline alone, of the compound of formula (I) as defined in the present invention alone and of the combination of doxycycline and said compound (I) against a bacterial strain of P. aeruginosa (PA01). More particularly, figure 1 indicates the concentration (µg/mL) of PAFA6, 13-19 required to restore doxycycline activity at 2 µg/mL against P. aeruginosa PA01. Figure 2 reports the antibacterial activity (MIC in µg/mL) of the compound of formula (I) as defined in the present invention alone and of the combination of doxycycline and said compound (I) against a bacterial strain of P. aeruginosa (PA01). More particularly, figure 2 indicates A) MIC (µg/mL) of derivatives PAFA2, 3, 5, 6, 10, 13-27 against P. aeruginosa PA01; and B) concentration (µg/mL) of derivatives PAFA2, 3, 5, 6, 10, 13-27 required to restore doxycycline activity at 2 µg/mL against P. aeruginosa PA01. Additionally, it is demonstrated that all the polyaminated fatty acid compounds as prepared above do not exhibit toxicity towards mammalian cells (data not shown).

Claims

1. Use of a polyaminated fatty acid compound responding to the following formula (I):

R¹-C( = O)-NH-(CR²R³)m-[X-(CR⁴R⁵)n]_P-NR⁶R⁷ (I) in which:

- R¹ represents a linear aliphatic chain comprising at least 7 carbon atoms, where the linear aliphatic chain is a mono- or polyunsaturated aliphatic chain, or a saturated aliphatic chain;

- R² and R³ represent, independently from each other, independently at each occurrence m, a hydrogen atom or a Ci-Cs alkyl group;

- R⁴ and R⁵ represent, independently from each other, independently at each occurrence n, independently at each occurrence p, a hydrogen atom or a Ci-Cs alkyl group;

- X represents, independently at each occurrence p, a -NR⁸- group or a divalent 5- to 7-membered heterocycloalkyl comprising at least one nitrogen atom; in which R⁸ represents a hydrogen atom, a Ci-Ce alkyl group, or -(CH2)_q- NH2 in which q represents an integer ranging from 1 to 5;

- R⁶ and R⁷ represent, independently from each other, a hydrogen atom, a Ci-Cs alkyl group, or R⁶ and R⁷ form together with the nitrogen atom to which they are attached a 5- to 7-membered heterocyclyl optionally substituted by one to three R⁹; where R⁹ represents -(CH2)u-NH2 in which u represents an integer ranging from 1 to 5;

- m is an integer ranging from 2 to 10;

- n represents, independently at each occurrence p, an integer ranging from 1 to 5; and

- p is an integer ranging from 0 to 4, a pharmaceutically acceptable salt and/or solvate thereof, as an adjuvant to an antibacterial drug.

2. Use according to claim 1, wherein the linear aliphatic chain R¹ is a mono- or polyunsaturated aliphatic chain.

3. Use according to claim 1 or claim 2, wherein R² and R³ represent, independently from each other, independently at each occurrence m, a hydrogen atom or a C1-C3 alkyl group.

4. Use according to any one of the preceding claims, wherein R⁴ and R⁵ represent, independently from each other, independently at each occurrence n, independently at each occurrence p, a hydrogen atom or a C1-C3 alkyl group.

5. Use according to any one of the preceding claims, wherein p ranges from 1 to 3.

6. Use according to any one of the preceding claims, wherein X represents, independently at each occurrence p, a -NR⁸- group in which R⁸ represents a hydrogen atom, a C1-C3 alkyl group, or -(CH2)_q-NH2 in which q represents an integer ranging from 1 to 3.

7. Use according to any one of the preceding claims, wherein R⁶ and R⁷ are hydrogen atoms.

8. Use according to any one of the preceding claims, wherein said polyaminated fatty acid compound is selected from the following compounds:

a pharmaceutically acceptable salt and/or solvate thereof.

9. A pharmaceutical composition comprising at least one polyaminated fatty acid compound as defined in any one of the preceding claims, and at least one antibacterial drug.

10. The pharmaceutical composition according to claim 9, wherein it comprises from 0.1 weight % to 50 weight % of said polyaminated fatty acid compound with respect to the total weight of the pharmaceutical composition.

11. The pharmaceutical composition according to claim 9 or claim 10, wherein the weight ratio of polyaminated fatty acid compound/antibacterial drug ranges from 0.2 to 2.

12. The pharmaceutical composition according to any one of claims 9 to

11, wherein the antibacterial drug is selected from tetracyclines and macrolides.

13. A pharmaceutical composition according to any one of claims 9 to 12, for use as a medicament.

14. The pharmaceutical composition for use according to claim 13, in the treatment of bacterial diseases; in particular caused by Gram-negative bacteria.

15. The pharmaceutical composition for use according to claim 13, for killing or inhibiting the growth of persister cells.

16. A kit comprising:

- a pharmaceutical composition comprising a polyaminated fatty acid compound as defined in any one of claims 1 to 8, and - a separate pharmaceutical composition comprising at least one antibacterial drug.

17. A polyaminated fatty acid compound selected from the following compounds of formula (I'-a):

a pharmaceutically acceptable salt and/or solvate thereof.

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