Combination of resorcinol derivatives for use as antibacterial agents

Abstract

The present invention relates to a combination of at least two different resorcinol derivatives, wherein one resorcinol derivative is a 4-alkylresorcinol of formula (I), a pharmaceutically acceptable salt, and / or a solvate thereof, and one resorcinol derivative is a 4-azoaryl resorcinol of formula (II), a pharmaceutically acceptable salt and / or solvate thereof, said combination for use as an antibacterial agent, a pharmaceutical composition comprising said combination, said pharmaceutical composition for use as a medicament, and said pharmaceutical composition for use in the treatment of bacterial or infectious diseases, in particular caused by Gram-positive bacteria.

Description

[0001]A COMBINATION OF RESORCINOL DERIVATIVES FOR USE AS ANTIBACTERIAL AGENTS The present invention relates to a combination of at least two differentresorcinol derivatives, wherein one resorcinol derivative is a 4-alkylresorcinolof formula (I), a pharmaceutically acceptable salt, and / or a solvate thereof, andone resorcinol derivative is a 4-azoaryl resorcinol of formula (II), apharmaceutically acceptable salt and / or solvate thereof, said combination for use as an antibacterial agent, a pharmaceutical composition comprising saidcombination, said pharmaceutical composition for use as a medicament, andsaid pharmaceutical composition for use in the treatment of bacterial orinfectious diseases, in particular caused by Gram-positive bacteria.GB1212694A describes treating an article made of a long-chain polymericthermoplastic material to render the surface of the article anti-microbial. One example of treatment consists of using a 4-alkylresorsinol compound asantimicrobial agent. Antibacterial properties against S aureus is describedwithout any other details. The introduction and increasing use of antibiotics for treatment have led to the rapid development and spread of antibiotic resistance in microorganisms, particularly in human pathogens. In addition, a tendency towards an increased number and severity of gram-positive infections has been observed in the lastdecade. Gram-positive bacteria are extremely important pathogens, both insideand outside the hospital environment. These pathogens include methicillin-resistant Staphylococcus aureus (MRSA), vancomycin-resistant Enterococcus(VRE), glycopeptide intermediate susceptible Staphylococcus aureus (GISA),vancomycin-intermediate and -resistant S aureus (VISA and VRSA), coagulase-negative staphylococcus (CONS or CNS) and penicillin-resistant Streptococcuspneumoniae (PRSP). All these pathogens have become a serious problem dueto their increased resistance rates, resulting in increasing morbidity andmortality because of limited treatment options. In particular, Staphylococcusaureus, the most common Gram-positive multidrug resistant pathogen causing nosocomial infections, is a major cause of morbidity and mortality worldwide. It is a frequent cause of both hospital-acquired and community-acquired infections in both healthy individuals and patients with risk factors or underlyingconditions. S. aureus can cause a wide range of infections, from mild skininfections to life-threatening diseases, including pneumonia, osteomyelitis, sepsis and bacteremia. Although few in number, new antibiotics have beendeveloped in the last few decades. As an example, Dalbavancin (trade name Dalvance in US, Xydalba in Europe), developed by Durata Therapeutics (acquired by Actavis in 2014), is a semisynthetic lipoglycopeptide which showspromising antibacterial effects against MRSA, S. pyogenes, S. agalactiae and E.faecalis strains susceptible to vancomycin.Drug combinations have also been proposed for antibacterial therapies.It is for example known to limit resistance by combining beta-lactams and beta-lactamase inhibitors. However, in view of the rapid emergence of multidrug-resistant bacteria, the development of antibacterial agents with novel modes of action that are effective against the growing number of resistant gram-positive bacteria, is of utmost importance. Thus, the aim of the present invention is to provide an antibacterial agent having improved antibiotic efficacy and / or reducing resistance mechanisms,preferably useful for the treatment of gram-positive bacteria, 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. Combination Afirst object of the present invention is a combination of at least twodifferent resorcinol derivatives, wherein one resorcinol derivative is a 4- alkylresorcinol responding to the following formula (I): *R1 is a linear or branched alkyl group comprising at least 4 carbonatoms, and preferably at least 6 carbon atoms, and * R2is an hydroxyl group (-OH) or an hydrogen atom, and preferably an hydrogen atom, apharmaceutically acceptable salt, and / or a solvate thereof, andwherein one resorcinol derivative is a 4-azoaryl resorcinol responding to in which : * R3is an aryl group or an heteroaryl group, said aryl or heteroaryl group being optionally substituted by one or more substituents selected from a nitrogroup, an alkyl group, a carboxylic acid group, and an hydroxyl group, and* R4 is an hydrogen atom or an alkyl group,a pharmaceutically acceptable salt and / or solvate thereof. Interestingly, the combination of these two resorsinol derivatives of formula (I) and (II) as defined in the present invention exihibits an antibacterialeffect against resistant bacteria strains, and more particularly against Gram- positive resistant bacteria strains.Additionally, such resorsinol derivatives of formula (I) and (II) as definedin the present invention are easy to prepare and they have low toxicity towardshumans and animals. Resorcinol derivative of formula (I) R1 preferably comprises at least 6 carbon atoms, more preferably at 8carbon atoms, more preferably at least 10 carbon atoms, and even morepreferably at least 11 carbon atoms.R1 preferably comprises at most 20 carbon atoms, more preferably atmost 18 carbon atoms, and even more preferably at most 16 carbon atoms.R1 preferably comprises from 4 to 16 carbon atoms, more preferably from6 to 14 carbon atoms, and even more preferably from 8 to 12 carbon atoms.R1is preferably a linear alkyl group. In the present invention, the term “linear alkyl group” means anunbranched alkyl group. In the present invention, the term “branched alkyl group” means an alkylgroup with alkyl branches comprising from 1 to 3 carbon atoms, and preferably1 or 2 carbon atoms. In one particularly preferred embodiment, compound (I) is selected from the following compounds: Resolcinol derivative of formula (II) The resorcinol derivative of formula (II) has an azo moiety -N=N-.Formula (II) encompasses unsaturation of Z configuration (cis configuration),unsaturation of E configuration (trans configuration), as well as mixture thereof.In other words, the resorcinol derivative of formula (II) may be in the form ofone isomer or a mixture of isomers. Preferably, the resorcinol derivative offormula (II) of the present invention is in the form of one isomer, and morepreferably has E configuration (trans configuration). Therefore the double bondbetween both nitrogen atoms of the azo moiety is represented by the followingsign: . In the present invention, the term “aryl group” refers to aromatic ringsor aromatic ring systems comprising from 6 to 12 carbon atoms, preferablyfrom 6 to 10 carbon atoms, and more preferably from 6 to 8 carbon atoms,having one or two rings which are fused together or linked covalently, wherein at least one ring is aromatic. In the present invention, the term “heteroaryl group” refers to aromaticring(s) or aromatic ring system(s) comprising at least 3 carbon atoms,preferably from 3 to 9 carbon atoms, more preferably from 3 to 7 carbon atoms,and even more preferably from 3 to 5 carbon atoms, said heteroaryl grouphaving one or several rings, wherein at least one ring is aromatic, and whereinat least one carbon atom in one of these rings is replaced by at least oneheteroatom which is a nitrogen atom. The heteroaryl group can have rings fused together or linked covalently. The heteroaryl group can comprise one or more additional heteroatoms, preferably selected from an oxygen atom, a nitrogen atom, a sulfur atom, and mixture thereof, and more preferably selected from a nitrogen atom, a sulfur atom, and mixture thereof. R3is an aryl group or an heteroaryl group, said aryl or heteroaryl groupbeing optionally substituted by one or more substituents selected from a nitrogroup, an alkyl group, a carboxylic acid group, and an hydroxyl group, andpreferably selected from a nitro group, an alkyl group and a carboxylic acidgroup. In one preferred embodiment, the aryl group R3 is a phenyl group.In one preferred embodiment, the heteroaryl group R3 is a pyridinylgroup or a thiazolyl group, and more preferably a pyridinyl group.The pyridinyl group is preferably a 2-pyridinyl group (i.e. the nitrogenatom of the pyridinyl group is in position 2 or in ortho position of the pyridinylgroup, where position 1 corresponds to the position of the carbon atom of thepyridinyl group covalently linked to the azo moiety). The thiazolyl group is preferably a 2-thiazolyl group (i.e. the azo moiety is covently linked to the carbon atom of the thiazolyl group which is placed between the sulfur and the nitrogen atoms of said thiazolyl group. In the present invention, said aryl or heteroaryl group can be substituted by one or more substituents selected from a nitro group, an alkyl group, a carboxylic acid group, and an hydroxyl group. In one preferred embodiment, R3 is a phenyl group, a pyridinyl group, ora thiazolyl group, optionally substituted with one or more substituents asdefined in the present invention. In the phenyl group, the substituent can be positioned in ortho position(2- or 6-position of the phenyl group, where position 1 corresponds to theposition of the carbon of the phenyl group covalently linked to the azo moiety),meta position (3- or 5-position of the phenyl group, where position 1corresponds to the position of the carbon of the phenyl group covalently linkedto the azo moiety) or para position, (4- position of the phenyl group, whereposition 1 corresponds to the position of the carbon of the phenyl groupcovalently linked to the azo moiety). In one preferred embodiment, said phenyl group is substituted in para position, and more preferably with a nitro group. In one preferred embodiment, said phenyl group is substituted by a nitrogroup, and preferably in para position. In one particularly preferred embodiment, R3is a phenyl group substituted by a nitro group in para position or a unsubstituted 2-pyridinylgroup or a unsubstituted 2-thiazolyl group.The alkyl group as the substituent of the aryl or heteroaryl group may be a linear or branched alkyl group comprising from 1 to 5 carbon atoms, and preferably from 1 to 3 carbon atoms, and more preferably 1 or 2 carbon atoms. The alkyl group as group R4may be a linear or branched alkyl group comprising from 1 to 5 carbon atoms, and preferably from 1 to 3 carbon atoms, and more preferably 1 or 2 carbon atoms. In one particularly preferred embodiment, compound (II) is selected from the following compounds: . Pharmaceutically acceptable salts include alkali metal and alkaline earth metal salts, and particularly the sodium and potassium salts. Pharmaceutically acceptable salts of resorcinol derivatives (I) and (II) ofthe invention may be prepared by reacting resorcinol derivatives (I) and (II)with the corresponding appropriate base or by means of a suitable ion exchangecolumn. 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 non-ionized. “Solvate” refers to molecular complex comprising a resorcinol derivative(I) or (II) along with stoichiometric or sub-stoichiometric amounts of one ormore 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 ofresorcinol derivatives (I) and (II) include conventional solvates such as thoseformed during the last step of preparation of these compounds due to the presence of solvents. In one preferred embodiment, the combination comprises a weight ratioresorcinol derivative (I) / resorcinol derivative (II) ranging from about 0.05 toabout 1.0, and more preferably from about 0.07 to about 0.5, and even morepreferably from about 0.1 to about 0.4.A second object of the present invention is a combination as defined in the first object of the present invention for use as an antibacterial agent. In the present invention, the term “antibacterial agent” 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 “resorcinol derivative of formula (I)”includes the resorcinol derivative of formula (I), as well as a pharmaceutically acceptable salt and / or solvate thereof. In the present invention, the term “resorcinol derivative of formula (II)”includes the resorcinol derivative of formula (II), as well as a pharmaceutically acceptable salt and / or solvate thereof. The combination as defined in the first object of the present invention isparticularly useful, for the treatment of bacterial diseases or infections, and inparticular caused by Gram-positive bacteria.Thus, the combination as defined in the first object of the presentinvention may be used in the treatment of bacterial diseases or infections, andin particular caused by Gram-positive 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. The combination of said resorcinol derivatives of formula (I) and (II) is administered in amounts that is more effective to inhibit bacteria than administration of the same amount of said resorcinol derivative of formula (I) without said resorcinol derivative of formula (II), or of the same amount of said resorcinol derivative of formula (II) without said resorcinol derivative of formula (I). The resorcinol derivative of formula (I) and resorcinol derivative of formula (II) administration can be performed simultaneously, separately, or sequentially. The invention also relates to a combination as defined in the first objectof the present invention, for medical use. “Gram-positive bacteria” refers to bacteria that retain the crystal violetstain used in the Gram staining. Gram-positive bacteria are characterized by abacterial cell wall composed of a thick mesh-like cell wall made of peptidoglycan (50–90% of cell envelope). The Gram-positive bacteria is preferably selected from Listeria bacteria,Staphylococcus bacteria, Streptococcus bacteria, Bacillus bacteria,Corynebacterium bacteria, Enterococcus bacteria, Corynebacterium,Enterococcus bacteria, and Clostridium bacteria, more preferably selected fromStaphylococcus bacteria, Enterococcus bacteria, and Streptococcus bacteria,and even more preferably selected from Staphylococcus bacteria andEnterococcus bacteria.In one preferred embodiment, the Staphylococcus bacteria isStaphylococcus aureus (SA), Staphylococcus haemolyticus (SH), orStaphylococcus epidermidis (SE).In one preferred embodiment, the Listeria bacteria is Listeria innocua (LI)or Listeria monocytogenes (LM).In one preferred embodiment, the Bacillus bacteria is Bacillus cereus (BC)or Bacillus subtilis (BS).In one preferred embodiment, the Enterococcus bacteria is Enterococcusfaecalis (EF), Enterococcus hirae (EH), or Enterococcus faecium (EFm).In one preferred embodiment, the Streptococcus bacteria isStreptococcus agalactiae (StA) or Streptococcus equinus (StE) (withoutmodification of CO2 atmospheric content).The resorcinol derivative of formula (I) as defined in the first object ofthe present invention can be prepared by Friedel Crafts reaction (fromresorcinol).The resorcinol derivative of formula (II) as defined in the first object ofthe present invention can be prepared by reacting a resorcinol derivative witha diazonium intermediate in basic medium, via an azo coupling reaction.A third object of the present invention is a pharmaceutical compositioncomprising a combination as defined in the first object of the present invention.Preferably, the pharmaceutical composition comprises at least oneresorcinol derivative of formula (I) as defined in the first object of the presentinvention and at least one resorcinol derivative of formula (II) as defined in thefirst object of the present invention. Indeed, said combination leads to a pharmaceutical composition havingimproved antibacterial activity, in particular against antibacterial drug-resistantbacteria, while guaranteeing low toxicity.The pharmaceutical composition preferably comprises a therapeutically effective amount of the combination. “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 comprisesfrom about 0.000016 weight % to about 1 weight % of said resorcinol derivativeof formula (I), and more preferably from about 0.0002 weight % to about 0.000256 weight % of said resorcinol derivative of formula (I), with respect tothe total weight of the pharmaceutical composition. These concentrationsenable antibacterial activity while guaranteeing low toxicity. In one preferred embodiment, the pharmaceutical composition comprisesfrom about 0.00005 weight % to about 1 weight % of said resorcinol derivativeof formula (II), and more preferably from about 0.000064 weight % to about0.001024 weight % of said resorcinol derivative of formula (II), with respect tothe total weight of the pharmaceutical composition. The pharmaceutical composition may further comprise a pharmaceutically acceptable carrier. “Pharmaceutically acceptable” means that the ingredients of thepharmaceutical composition are compatible with each other and not deleteriousto 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 any and 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. Afourth object of the present invention is a pharmaceutical compositionas defined in the third object of the present invention for use as a medicamentor for medical use. Afifth object of the present invention is a pharmaceutical composition asdefined in the third object of the present invention for use in the treatment ofbacterial diseases, in particular caused by Gram-positive bacteria.The bacterial disease (respectively the Gram-positive bacteria) is asdefined in the second object of the invention.The present invention further relates to a method for treating a bacterialdisease in a subject in need thereof, comprising administering to the subject apharmaceutical composition as defined in the third object of the presentinvention. 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 thethird object of the present invention.The present invention further relates to the use of a pharmaceuticalcomposition as defined in the third object of the present invention, for themanufacture of a medicament for the treatment of a bacterial disease in asubject in need thereof. The present invention further relates to the use of a pharmaceuticalcomposition as defined in the third object of the present invention, as describedherein, 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 also relates to the use of a pharmaceuticalcomposition as defined in the second object of the present invention, fortreating a bacterial disease in a subject in need thereof.The present invention also relates to the use of a pharmaceuticalcomposition as defined in the third object of the present invention, for treatinga chronic infection, a relapsing infection, a recalcitrant infection, a persistentinfection, a persister related-infection, a persister related-chronic infection, apersister related-relapsing infection, a persister related-recalcitrant infection,or a persister related-persistent infection 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 ofsuch microorganism. “Bacterial infection” ou “bacterial disease” is a pathologiccondition 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, pneumonia; and skin infection (softtissues). In one preferred embodiment, the bacterial disease is caused by Gram-positive 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. A sixth object of the present invention is the non-therapeutic use of acombination as defined in the first object of the present invention, as anti- infective agent, preferably for the disinfection of a surface and / or the purification of a liquid. In this sixth object, the combination is not used or applied to a humanor an animal. As a result, the combination is applied to an object such as amedical device, for example a protheses, or to a surface of said object fordisinfection of such object or surface. Alternatively, the combination is mixedwith a liquid or a fluid for purification of such liquid or fluid. A seventh object is at least one resorcinol derivative of formula (II) as defined in the first object of the present invention for use as an adjuvant to an antibacterial drug selected from resorcinol derivatives of formula (I) as defined in the first object of the present invention. The resorcinol derivative of formula (II) as defined in the first object ofthe present invention is used as an adjuvant to a resorcinol derivative offormula (I) as defined in the first object of the present invention. As mentioned in the background art, an adjuvant is also called "resistance circuit breaker", “chemosensitizer” or "(antibiotic) potentiator”. The resorcinol derivative of formula (I) and the resorcinol derivative offormula (II) are administered in amounts that together are more effective toinhibit bacteria than administration of the same amount of the resorcinol derivative of formula (I) without the resorcinol derivative of formula (II). A potentiator or restoration effect is observed for the resorcinol derivative of formula (II) when a MIC ratio is greater than 1, preferably greater than 10, more preferably greater than 100; and even more preferably greater than 1000, where the MIC ratio = MIC of said resorcinol derivative of formula (I)alone for a given strain (in µM) / MIC of said resorcinol derivative of formula (I)in the presence of said resorcinol derivative of formula (II) (in µM). The present invention is illustrated in more detail in the examples below, but it is not limited to said examples. Examples Materials 4-dodecylresorcinol responding to the following formula:was used ascompound (I) and was purchased to Sigma Aldrich.4-(4-nitrophenylazo)resorcinol responding to the following formula: was used as compound (II) and waspurchased to ThermoScientific.Unless mentioned otherwise, compounds were directly used “as such” in the examples below. The bacterial strains used in the examples below are Staphylococcusaureus CIP 53.156 (this strain is reference strain for standard NF EN 1276),Staphylococcus aureus CIP 111683 (methicillin resistant, erythromycin-resistant and kanamycin-resistant) isolated from nose,Staphylococcus.haemolyticus isolated from goat, Enterococcus faecalis CIP76.117, Enterococcus hirae CIP 58.55, and Enterococcus faecium (penicillinresistant) (isolated from goat). Bacteria strains are cryoconserved (-80°C). Before the antibacterial test, bacterial strains are reactived in mueller hinton broth (2 growth cycles). Toperfom the test a standart inoculum is prepared to obtain bacterial brothconcentrated around 106and 108UFC / mL. 200 µL of bacterial broth aredispensed in 96 wellplate. Growth controls are performed with 2 µL of water,absolute ethanol, or 50% ethanol. 2 µL of resorcinol derivatives is distributedto 96 wellplate before adding bacterial broth. Resorcinol derivatives solutionsand dilutions are performed as antibiotics solutions as described below.The antibiotics used as reference in the examples below are: Fusidic acid,Chloramphenicol, Streptomycin and Kanamycin, Ampicillin and Erythromycinpurchased from Sigma, ThermoScientific or Apollo Scientific. These antibioticswere dissolved in absolute ethanol, 50% ethanol, or distilled water accordingto the antibiotics solubility. Stock solution is concentrated at 102.4 mg / mL. Asof each solution stock two-fold dilution series in water are performed (from102,4 mg / mL to 0,00001 mg / mL). All dilutions range of each antibiotics aredistributed in the 96 platewell before adding bacterial broth. Example 1: antibacterial activity of the combination of the present invention The antibacterial activity of resorcinol derivative (I), resorcinol derivative(II) and the combination of said resorcinol derivatives (I) and (II) wasmeasured using a microplate reader “infinite mplex tecan”, measuring opticaldensity at 600 nm. Double validation was performed with iodonitrotetrazoliumwith optical density measure at 490 nm after reaction.1.1 preparation of a preculture A negative control which corresponds to Mueller Hinton broth with 2 µL of ethanol and inoculum and a positive control which corresponds to Mueller Hinton broth with 2 µL of antibiotic and inoculum were prepared. The tubes were incubated in an “Memmert” incubator with a “seastarshaker” 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. 1.2 measurement of antibacterial activity To determine MIC (90% Inhibitory Concentration (IC90)), after incubationtime optical density is measured at 600 nm with “tecan infinite mplex reader”. After the first measure (OD 600nm) a second one is performed adding a iodonitrotetrazolium solution to the microplate. The reaction with respiration evidence (succinate deshydrogenase) products formazan. Formazan quantification (presence / absence) is performed at 490 nm. The results are expressed as dose-response relationships, modeled by a non-linear regression analysis using TableCurve software. The 90% InhibitoryConcentration (IC90) represents the concentration of compound capable ofreducing cell viability by 90%. Table 1 below reports the antibacterial activity of (I), (II) and (I) + (II)with respect to S. aureus strains: IC90 (µg / ml) Name S. aureus (CIP 53.156)(I) 4(II) 1(I) + (II) 0.16 / 0.64TABLE 1 Figure 1 reports the results of 90% Inhibitory Concentration (IC90) for S.aureus and other strains SARM and S. Haemolyticus for compound (I) alone,compound (II) alone and mixture of compounds (I) + (II). Figure 2 reports the results of 90% Inhibitory Concentration (IC90) for S.aureus and other strains SARM and S. Haemolyticus for Streptomycin,Kanamycin, Fusidic acid, Chloramphenicol and mixture of compounds (I) + (II). Figure 3 reports the results of 90% Inhibitory Concentration (IC90) for E.faecalis, E. faecium and E. hirae for for compound (I) alone, compound (II)alone and mixture of compounds (I) + (II). Example 2: toxicity of the combination of the present inventionIn order to consider the use of these two resorcinol derivatives (I) and(II) as a cutaneous antibiotic mixture, the OECD 439 skin irritation test wascarried out. The aim of this test is to determine whether the presence of thesetwo resorcinol derivatives (I) and (II) can alter the cell viability of areconstructed epidermis. The model used is the SkinEthic Reconstructed Human Epidermis (RHE). According to OECD 439, a molecule is classified as irritant if cell viability is reduced by 50% or more. In addition, it is accepted that a non- irritant molecule cannot be corrosive. Table 2 below reports viability of SkinEthic Reconstructed HumanEpidermis (RHE) in the presence of two resorcinol derivatives (I) and (II). Strains Concentration Viability (% by mass)(%, n = 2)SD (%) Classification1 105.3 5.3 non irritant(I) 0.05 92.4 0.3 non irritant1 77.3 9.2 non irritant(II) 0.05 108.5 1 non irritantTABLE 2

Claims

CLAIMS 1. A combination of at least two different resorcinol derivatives, whereinone resorcinol derivative is a 4-alkylresorcinol responding to the following formula (I):in which: * R1is a linear or branched alkyl group comprising at least 4 carbon atoms, and * R2is an hydroxyl group (-OH) or an hydrogen atom, and preferably an hydrogen atom, apharmaceutically acceptable salt, and / or a solvate thereof, andwherein one resorcinol derivative is a 4-azoaryl resorcinol responding to the following formula (II),in which * R3is an aryl or heteroaryl group, said aryl or heteroaryl group being optionally substituted by one or more substituents selected from a nitro group,an alkyl group, a carboxylic acid group, and an hydroxyl group, and* R4 is an hydrogen atom or an alkyl group,a pharmaceutically acceptable salt and / or solvate thereof.

2. The combination according to claim 1, wherein R1 is a linear orbranched alkyl group comprising at least 6 carbon atoms.

3. The combination according to claim 1 or 2, wherein R1 is a linear alkylgroup.

4. The combination according to any one of the preceding claims, whereinthe aryl group R3 is a phenyl group.

5. The combination according to any one of the preceding claims, whereinthe heteroaryl group R3 is a pyridinyl group or a thiazolyl group.

6. The combination according to any one of the preceding claims, whereinR3is a phenyl group substituted by a nitro group in para position or aunsubstituted 2-pyridinyl group or an unsubstituted 2-thiazolyl group.

7. The combination according to any one of the preceding claims, whereinthe combination comprises a weight ratio resorcinol derivative (I) / resorcinolderivative (II) ranging from 0.05 to 1.0.

8. A combination as defined in any one of claims 1 to 7, for use as anantibacterial agent.

9. A pharmaceutical composition comprising a combination as defined inany one of claims 1 to 7.

10. The pharmaceutical composition according to claim 9, wherein itcomprises from 0.000016 weight % to 1 weight % of said resorcinol derivativeof formula (I).

11. The pharmaceutical composition according to claim 9 or 10, whereinit comprises from 0.00005 weight % to 1 weight % of said resorcinol derivativeof formula (II).

12. A pharmaceutical composition as defined in any one of claims 9 to11, for use as a medicament.

13. A pharmaceutical composition as defined in any one of claims 9 to11, for use in the treatment of bacterial diseases, in particular caused by Gram-positive bacteria.

14. Non-therapeutic use of a combination as defined in any one of claims1 to 7, as anti-infective agent, preferably for the disinfection of a surface and / or the purification of a liquid.

15. At least one resorcinol derivative of formula (II) as defined in anyone of claims 1 and 4 to 7, for use as an adjuvant to an antibacterial drugselected from resorcinol derivatives of formula (I) as defined in any one of claims 1 to 3.

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