EP3193860A1 - Antimicrobiens potentialises - Google Patents

Antimicrobiens potentialises

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Publication number
EP3193860A1
EP3193860A1 EP15762653.2A EP15762653A EP3193860A1 EP 3193860 A1 EP3193860 A1 EP 3193860A1 EP 15762653 A EP15762653 A EP 15762653A EP 3193860 A1 EP3193860 A1 EP 3193860A1
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EP
European Patent Office
Prior art keywords
alkyl
antimicrobial agent
compound
antimicrobial
alkenyl
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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Application number
EP15762653.2A
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German (de)
English (en)
French (fr)
Inventor
Nicolas Tesse
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SEPTEOS
Original Assignee
SEPTEOS
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Publication of EP3193860A1 publication Critical patent/EP3193860A1/fr
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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/14—Esters of carboxylic acids, e.g. fatty acid monoglycerides, medium-chain triglycerides, parabens or PEG fatty acid esters
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
    • A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
    • A61K31/22—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin
    • A61K31/222—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin with compounds having aromatic groups, e.g. dipivefrine, ibopamine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
    • A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
    • A61K31/216—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acids having aromatic rings, e.g. benactizyne, clofibrate
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
    • A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
    • A61K31/235—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids having an aromatic ring attached to a carboxyl group
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/407—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with other heterocyclic ring systems, e.g. ketorolac, physostigmine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4164—1,3-Diazoles
    • A61K31/4178—1,3-Diazoles not condensed 1,3-diazoles and containing further heterocyclic rings, e.g. pilocarpine, nitrofurantoin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/42—Oxazoles
    • A61K31/424—Oxazoles condensed with heterocyclic ring systems, e.g. clavulanic acid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/425—Thiazoles
    • A61K31/429—Thiazoles condensed with heterocyclic ring systems
    • A61K31/43—Compounds containing 4-thia-1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula, e.g. penicillins, penems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/54—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame
    • A61K31/542—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/545—Compounds containing 5-thia-1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. cephalosporins, cefaclor, or cephalexine
    • A61K31/546—Compounds containing 5-thia-1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. cephalosporins, cefaclor, or cephalexine containing further heterocyclic rings, e.g. cephalothin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/65—Tetracyclines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7028—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages
    • A61K31/7034—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/10—Antimycotics
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
    • Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
    • Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Definitions

  • the subject of the invention is the compounds of formula (I), used at a dose where they no longer exhibit antimicrobial properties, for their use as agents intended for the potentiation of the antimicrobial active agents with which they are co-administered.
  • the combination "potentiator (s) + antimicrobial (s)” is intended to prevent and / or treat bacterial and fungal infections in humans or animals.
  • the invention also relates to a method for potentiating antimicrobials in which is co-administered with said antimicrobial compound (or more) of formula (I).
  • the compound of formula (I) is used at a dose where it is inactive alone.
  • the invention aims to provide solutions to the problems related to the decline or loss of antimicrobial activity during their period of commercial and medical use.
  • the invention is therefore a solution that applies to current antimicrobials and will apply to future antimicrobials.
  • microbes bacteria and fungi
  • the invention describes the use of compounds of formulas (I) for potentiating antimicrobials. Unexpectedly, these compounds have demonstrated their ability to potentiation of the effect of antimicrobials at low doses (from 0.01 to 100 mg / l) very far from those where they can, alone, have antimicrobial properties. Consequently, the antimicrobials with which the compounds of formulas (I) are co-administered have, because of the potentiation, an activity greater than that usually observed.
  • the invention aims to potentiate the "antimicrobials", usable in humans or animals and not all compounds that have “antimicrobial properties", which they are often not administrable to humans or animals because of too high a toxicity or a threshold of antimicrobial activity too high requiring doses incompatible with the health.
  • any molecule has, in absolute terms, antimicrobial properties.
  • the antimicrobial properties of a molecule must therefore be evaluated in relation to the minimum concentration that inhibits the bacteria.
  • the invention is based on the surprising discovery that compounds which have antimicrobial properties at very high doses (level incompatible with a use in medicine for this purpose) and whose minimum inhibitory concentration (MIC) exceeds 5000 mg / L preferably greater than 10,000 mg / L exhibit potentiating effects at low doses (0.01 to 100 mg / l). At these doses, it becomes possible to use the compounds (I) in humans or animals.
  • cinnamyl acetate or benzyl benzoate which has antimicrobial properties at a concentration of about g / L (MIC greater than 10,000mg / l is greater than 1% , depending on the strains), shows effects of potentiation of antibiotics at these concentrations close to the MIC (1 to 3 dilutions).
  • benzyl benzoate When its concentration is lowered below the MIC, benzyl benzoate no longer potentiates antimicrobials (see Example 1-10). Then, very surprisingly, it was found that by significantly decreasing the concentration of benzyl benzoate, 10 to 50 times less than the MIC, benzyl benzoate again has potentiating effects on a very large number of antibiotics on a very large number of strains, this time at doses compatible with medical use.
  • the potentiating effect observed with the compound according to the invention is not specific for a particular mechanism of resistance but is observed on various strains, whether they have, or have not, developed. one or more distinct resistance mechanisms.
  • the prior art is consistent with the compounds (I) because they belong to chemical classes that are well studied in many fields.
  • the compounds (I) within the scope of the present invention have the following characteristics which make it possible to exclude them from the prior art and which make it possible to envisage their use as a potentiator of antimicrobials administered to humans and animals:
  • the concentration used to observe antimicrobial activity is not compatible with future use in humans or animals, particularly during systemic application.
  • medical use is envisaged while the measured effective concentrations (of the order of several mg / ml) are incompatible with this use.
  • the antimicrobial effects measured have very often been for levels of essential oil, or its active compound, of the order of several mg / ml.
  • 1 mg / ml corresponds to 1 g / l or 1 g / kg or else 0.1%. If the MIC was 1 mg / ml, depending on the pharmacokinetic parameters, at least 1 g / kg / day body weight should be administered.
  • the effective dose for a cow should be at least 500 g / d and at least 60 g / d for man (this corresponds to the minimum dose since it is assumed here that the product is fully absorbed and distributed in the organization). These doses too important are not possible for safe use in therapy.
  • WO 99/66796 (Wisconsin Alumni Research Foudation) describes a method for sensitizing microbial cells against antibacterial compounds comprising a step of contacting with an antibacterial compound and a sesquiterpenoid, to improve the effect of antibacterial compound.
  • the MICs were determined with the agar diffusion method, unsuited to the volatile and hydrophobic nature of the compounds (I) and related families.
  • This method consists of depositing paper disks impregnated with known quantities of test compounds on an agar seeded with the bacterium to be studied. A concentration gradient of the compound around the agar is established on the agar each disc; after 18 hours the diameter of the inhibition halo is measured.
  • This method is however not reliable for hydrophobic compounds which, because of very different surface tensions and contact angles on the hydrophilic surfaces, interfere with the formation of the concentration gradient in the agar. In some areas, the concentration of test compounds is much higher than the theoretical concentration. Thus, the tests can not be quantitative, when they can be qualitative.
  • there is a dilution of the hydrophobic compound to be tested in ethanol without however correcting the result while ethanol is an antibacterial and volatile compound.
  • Essential oils and their derivatives are usually described as being low in toxicity, which is often true in food or perfumery applications but erroneous in the context of therapeutic administration.
  • WO2006 / 120567 (Advanced Scientific Developments) describes pharmaceutical compositions comprising at least one therapeutic substance that is active and described as non-toxic, chosen from carveol, thymol, eugenol, borneol, carvacrol, alpha-ionone and beta-ionone, and their isomers. , derivatives and mixtures, and comprising, as the second active therapeutic substance, an antibiotic.
  • Carveol, thymol, eugenol, borneol, carvacrol, alpha-ionone, or beta-ionone used alone, exhibit antibacterial activity and many of them also pose toxicity problems, ignored in this application.
  • carvacrol has the following toxicity data: LD 50
  • the main component tea tree essential oil is terpinen-1-ol.
  • micro-organism any living organism, invisible to the naked eye because of its small size.
  • Organism means any biological (living) animal or plant entity capable of birth, development and normally reproduction.
  • microbe includes the definition of microorganism, limited to the medical field to which the invention refers.
  • microbes are living microorganisms potentially pathogenic (bacteria, fungi, yeast and mycobacteria). The term therefore excludes inert pathogens such as viruses and prions.
  • antimicrobial any compound intended to be administered to humans or animals capable of killing or inhibiting the growth of microbes.
  • pharmaceutically acceptable salts of these antimicrobials are also included in this definition. This includes, for example, the sodium, potassium, calcium, etc. salts. and the amine salts of procaine, dibenzylamine, ethylendiamine, ethanolamine, methylglucamine taurine, etc., as well as acid addition salts such as hydrochlorides and basic amino acids.
  • antibiotics to be administered to humans or animals capable of killing or inhibiting the growth of microbes.
  • the pharmaceutically acceptable salts of these antimicrobials are also included in this definition. This includes, for example, the sodium, potassium, calcium, etc. salts. and the amine salts of procaine, dibenzylamine, ethylendiamine, ethanolamine, methylglucamine taurine, etc., as well as acid addition salts such as hydrochlorides and basic amino acids.
  • the term includes antibiotics (t
  • Antimicrobial properties means the properties of any substance capable of destroying or inhibiting the growth of microbes. Products with antimicrobial properties include antimicrobials and biocides.
  • biocide includes products with antimicrobial properties intended to be applied to inert systems (viruses and prions).
  • antibacterial properties and “antifungal properties” is meant not only the bactericidal and fungicidal properties characterized by the destruction of bacteria and fungi (and yeasts, mycobacteria), but also the bacteriostatic and fungistatic properties, characterized by the inhibition of the growth of said bacteria and fungi (and yeasts, mycobacteria). Products with antibacterial or antifungal properties include antimicrobials.
  • antibiotic-resistant bacterium is intended to mean a bacterium resistant to at least one, in particular at least two, in particular at least three or even at least four antibiotics or family (s). antibiotic, conventionally used.
  • multi-resistant bacterium means a bacterium resistant to several antibiotics, in particular for which the strain should be sensitive, or a priori sensitive, especially a bacterium that has at least two unnatural resistances. .
  • Microbial infection in the sense of the present invention refers to an infection caused by one or more microbial strains and includes phases ranging from colonization of the host to pathological phases.
  • the term “microbial infection” therefore includes any adverse effect, clinical sign, symptom or any disease occurring in humans or animals following colonization by the microbe.
  • terpenoid is meant according to the invention any compound comprising a skeleton close to a terpene.
  • Terpene refers to a derivative of isoprene which is obtained biologically by the condensation of C5 units, leading for example to monoterpenes, sesquiterpenes.
  • Near is meant that the backbone is similar to a terpene or different in that at least one alkyl substituent, normally present, may be absent or carried by another atom.
  • the backbone can also be substituted by various radicals such as aliphatic radicals, saturated or unsaturated, linear or cyclic (alkyl, alkenyl, alkylene), oxy, aldehydes, esters, alcohols, ethers and their sulfur or nitrogen equivalents.
  • the terpenoid can advantageously be of natural origin.
  • phenylpropanoide any compound comprising a backbone close to a phenylpropane.
  • Phenylpropane refers to a derivative obtained by biological synthesis from phenylpropane and resulting in derivatives C6 (aromatic) -C3 (aliphatic) or C6 (aromatic) -Cl (aliphatic) and corresponding lactones.
  • near is meant that the backbone is similar to a phenylpropane, in particular the phenyl unit, or different in that at least one alkyl substituent, normally present, may be absent or carried by another atom.
  • the backbone can also be substituted by various radicals such as aliphatic radicals, saturated or unsaturated, linear or cyclic (alkyl, alkenyl, alkylenes), oxy, aldehydes, esters, alcohols, ethers and their sulfur equivalents or nitrogen.
  • the phenylpropanoid can advantageously be of natural origin.
  • prophylaxis or “prevent an infection” as used in this application refers to any degree of delay in the onset of clinical signs or symptoms of infection, as well as any degree of inhibition of severity of clinical signs or symptoms of infection, including but not limited to, total prevention of said infection.
  • This prophylactic administration can take place before, during or after the act likely to cause an infection (particularly a nosocomial infection) in order to prevent, improve, and / or reduce the severity of any subsequent infection.
  • treatment in the context of the present application implies that the antimicrobial and the compound according to the invention are co-administered to a subject (human or animal) at the time of colonization or after contamination or suspicion of contamination by a microbial strain likely to cause an infection such as a nosocomial infection.
  • treatment or “treating an infection” therefore includes: any curative effect (inhibition of growth or destruction of the microbe) obtained by virtue of the antimicrobial co-administration + compound according to the invention as well as the improvement of the clinical signs or symptoms observed as well as the improvement of the condition of the subject.
  • the antimicrobial-compound co-administration according to the invention can indeed also make it possible to slow the progression of a microbe and / or completely or partially prevent a microbial infection from spreading to the surrounding tissues and beyond.
  • co-administered means that the antimicrobial (or the antimicrobial mixture) and the compound according to the invention (or the mixture of compounds according to the invention) are administered in combined or juxtaposed form to the subject (human or animal).
  • the combination includes any combination drug, any pharmaceutical composition, any pharmaceutical kit, and any drug comprising (i) at least one antimicrobial and (ii) at least one compound of the invention.
  • Compounds (i) and (ii) may be present as a mixture or in the form of separate formulations or compositions in said combination.
  • the combination may also comprise several antimicrobials, for example 2, 3 or 4 or more antimicrobials, and / or more compounds according to the invention, in particular 2 or 3 or more compounds according to the invention. These constituents form a functional unit because of a common indication, which is the implementation of an antimicrobial treatment.
  • This combination therapy is more specifically intended for the prophylaxis and / or treatment of microbial infections and diseases, in particular nosocomial infections.
  • Co-administration can be simultaneous or spread over time.
  • the term "simultaneous" means that the antimicrobial (or the antimicrobial mixture) and the compound according to the invention (or the mixture of compounds according to the invention) are administered at the same time, at the same time, to a subject (male or female). animal). These compounds can be administered in the form of a mixture or, simultaneously but separately, in the form of separate compositions.
  • sequential administration means that the antimicrobial (or the antimicrobial mixture) and the compound according to the invention (or the mixture of compounds according to the invention) are administered not simultaneously but separately in time, one after the other.
  • an antimicrobial means that the use of a compound according to the invention makes it possible to obtain a prophylactic or therapeutic effect superior to the prophylactic or therapeutic effect obtained by using the one or more antimicrobials alone. This can be expressed in different, alternative or cumulative ways:, increased antimicrobial effect, decreased antimicrobial antimicrobial dose, reduced MIC. In addition, the potentiation makes it possible to reduce or annihilate the appearance of resistance.
  • the expression "decrease the amount of antimicrobial used” means that the use of the compound according to the invention makes it possible to use an amount of antimicrobial less than the quantity of antimicrobial normally required to obtain a given therapeutic or prophylactic effect when the antimicrobial is administered alone.
  • the decrease in the amount of antimicrobial used may be more or less important; it is preferably at least 10%, and more preferably at least 20%, still more preferably at least 40%, or even 50% or more of the amount normally required to achieve an effect. therapeutic or prophylactic.
  • MIC means "minimal inhibitory concentration", which is the lowest concentration of substance at which microbial growth is no longer observed after 18 to 24 hours of contact under conditions conducive to microbial growth. Measurement of minimum inhibitory concentration are made in solid agar medium according to the international standards in force (CLSI M7-A9 Jan 12 standards): dispersion of test compounds in a Mueller Hinton agar agar. An adaptation relating to the hydrophobicity of the compounds and compositions is however necessary to disperse them in the medium: dilution in a solvent.
  • the compounds and compositions incorporated in the agar may be first diluted in one or more solvents (Tween® 80 diluted in water, Tween® 80 diluted in propylene, DMSO diluted in water).
  • the strains are deposited on the surface of the agar with a steers apparatus.
  • different methods of dissolving the products are tested in parallel to circumvent the problems of water / solvent distribution coefficient of the molecules (antimicrobial and potentiator) while the bacteria grow in the single aqueous phase.
  • the technical constraint will not intervene in the in vivo tests.
  • the same dilution methods can be implemented in a liquid medium (microplates and tubes). The same methodology is implemented with fungi.
  • MICs 50 and MIC 90 respectively represent the concentrations which inhibit 50% and 90% by number of the strains of the same genus.
  • alkyl denotes an unsaturated aliphatic hydrocarbon chain containing from 1 to 6 carbon atoms (Ci-C 6 ) or from 1 to 4 carbon atoms (C 1 -C 4 ), linear or branched.
  • alkyl radicals having from 1 to 4 carbon atoms mention may be made of methyl, ethyl, propyl, butyl, isopropyl, 1-methyl-ethyl, 1-methylpropyl and 2-methylpropyl radicals.
  • alkyl radicals containing from 1 to 6 carbon atoms mention may also be made of the pentyl, hexyl, 1-methyl-butyl, 1-methyl-pentyl, 2-methyl-butyl and 2-methyl-pentyl radicals. methyl-butyl, 3-methyl-pentyl, 4-methyl-pentyl or 1-ethyl-propyl, 1-ethyl-butyl, 2-ethyl-butyl.
  • alkoxy denotes an O-alkyl radical, (where alkyl is as defined above), for example methoxy or ethoxy.
  • alkyl (s) and / or “alkenyl (s)” and / or “alkoxy (s)” radicals carried by the same backbone may together form a ring or a heterocyl (in particular a lactone).
  • alkylene refers to the hydrocarbon chain formed when two "alkyl (s)” and / or “alkenyl (s)” radicals are bonded to each other.
  • cycloalkyl is intended to mean any saturated or unsaturated, but not aromatic, hydrocarbon ring of 3 to 7 members, in particular of 5 or 6 members, such as cyclopentyl and cyclohexyl.
  • cycloheteroalkyl is intended to mean any hydrocarbon ring, saturated or unsaturated, but not aromatic, of 5 to 7 ring members, containing one or more heteroatoms, such as, for example, sulfur or carbon atoms. oxygen.
  • oxy denotes a ketone function and "CHO" designates an aldehyde function.
  • log P is an equilibrium concentration ratio of a non-ionized compound in two immiscible solvent phases (water and n-octanol).
  • the invention relates to a potentiated antimicrobial agent for its use in the treatment of a microbial infection, characterized in that in combination with the antimicrobial agent is used a compound corresponding to the following formula I:
  • the dotted lines represent links that may be absent or present, provided that two double bonds are not adjacent
  • n 0 or 1
  • Ri represents H or an alkyl radical Ci-C 6 alkenyl or C 2 -C 6
  • R 2 represents H or OH, 0-CO- (C 1 -C 4) alkyl, 0- (C 1 -C 4) alkyl-C 6, N-alkyl (Ci-C 6 ) 2 , advantageously R 2 represents H
  • R 3 represents H or an OH, O-CO- (C 1 -C 4 alkyl), O- (C 1 -C 4 alkyl), O- (C 2 -C 4 ) alkenyl radical, advantageously R 3 represents H R 2 and R 3 may together form the corresponding lactone
  • Z represents a radical CO-R 5 with R 5 which represents an OH, O-C 1 -C 6 alkyl, O- (C 1 -C 4 alkyl) -phenyl or O-C 2 -C 6 alkenyl radical, preferably an O-alkyl radical Ci-C 6, O- (Ci-C 4) -p enyl, O-alkenyl, C 2 -C 6,
  • Z represents a radical CO-R 5 or CH 2 -O-CO- (C 1 -C 6 alkyl) or CH m R 7 or C 4 -C 10 alkyl or C 4 -C 10 alkenyl, C 4 -C 4 alkyl radicals; C 10 or C 4 -C 10 alkenyl may be linear or branched, optionally substituted with OH; advantageously these radicals are not substituted
  • R 5 represents OH, O-alkyl, Ci-C 6, O- (Ci-C 4) phenyl, 0- (alkenyl C 2 -C 4 alkyl) -phenyl, O- alkenyl C 2 -C 6 , advantageously an O-C 1 -C 6 alkyl, O- (C 1 -C 4 ) alkylphenyl, O-C 2 -C 6 alkenyl radical, or with R 5 which represents H at the provided that R 4 represents an alkyl radical in C 2 -C 6, or R 2 represents an alkyl radical in C 2 -C 6 alkyl, N- (alkyl-C 6) 2
  • o with m is 1 or 2; m is 2 if the bond between Ci and C 2 is double
  • R 7 represents H or a C 1 -C 6 alkyl radical
  • R 4 represents H or a C 1 -C 6 alkyl radical
  • compound of formula (I) antimicrobial agent, varying from 8: 1 to 1:10, and in that the antimicrobial agent is not a terpenoid or a phenylpropanoid.
  • the antimicrobial agent is advantageously an active ingredient of Western conventional medicine, as will be described later.
  • the antimicrobial agent is not a terpenoid or phenylpropanoid, such as an essential oil extract or an essential oil component.
  • the compound mass ratio of formula (I): antimicrobial agent more preferably from 4: 1 to 1:10, more preferably from 1: 1 to 1:10, still more preferably from 1: 1 to 1: 5.
  • the mass ratio corresponds to the ratio of doses in mg / kg of the compound and the antimicrobial agent to be administered to humans or animals.
  • in vitro concentration of inactive compound which is observed a potentiating effect, is far removed from the threshold of antimicrobial properties (MIC), when antimicrobial properties are observed.
  • MIC threshold of antimicrobial properties
  • the concentration in vitro is at least 10-fold, advantageously at least 20-fold, more preferably at least 50-fold, still more preferably at least 100-fold less than the MIC.
  • x is greater than or equal to 100, preferably 1,000, more preferably x is from 2,000 to 10,000, or even greater than 50,000.
  • the doses of compound (I) are less than 100 mg / l, advantageously less than 64 mg / l, more advantageously between 0.01 and 25 mg / l, more advantageously between 1 and 16 mg / l. .
  • the concentration, per unit dose per kilogram, of compound of formula (I) is advantageously less than 100 mg, more advantageously less than 64 mg.
  • the compounds (I) can be used at a low concentration (in vitro at concentrations of the order of ⁇ / ⁇ 1) to potentiate the antimicrobials, which is entirely compatible with future use in humans or animal (especially if systemic administration is sought).
  • the potentiating compound according to the invention is advantageously administered at a concentration such that its maximum serum concentration is less than 250 mg / l, advantageously less than 150 mg / l, more advantageously between 10 and 150 mg / l after administration.
  • the compound can be administered to humans and animals, including systemically, and does not present major adverse effects, in particular carcinogenicity or genotoxicity.
  • the mass ratio compound according to the invention (or mixture of compounds according to the invention): antimicrobial depends in each case on the antimicrobial used and it will be adapted case by case.
  • the dose of compound of formula (I) may vary between 300 and 850 mg per dose, or less.
  • the dose of compound of formula (I) may vary between 0.1 and 0.8 MUI, or even less.
  • Another formulated, the invention relates to a method for potentiating the antimicrobial activity of an antimicrobial independently of the resistance mechanism comprising the following steps:
  • the invention also relates to a method for treating and / or preventing microbial infection in a subject, comprising co-administration in the subject suffering from said microbial infection of an antimicrobial and a compound of formula (I).
  • the compound and antimicrobial agent are suitable for simultaneous administration, separate or spread over time to humans or animals.
  • the antimicrobial is preferably an antibiotic. It can also be an antifungal.
  • the compounds of formula (I), used at this low concentration are capable of potentiating the activity of antimicrobials.
  • the use of these potentiators advantageously makes it possible to use said antimicrobial at a lower concentration and / or at the usual concentration while having a higher activity than the antimicrobial alone at the same dose (increase in the intensity of the effect or kinetics of the effect).
  • the invention makes it possible in particular:
  • B / to increase the effect at constant dose increase of the capacity of an antimicrobial to inhibit / destroy the sensitive germs (improvement of the kinetics of the effect, the intensity of the effect, and widening of the spectrum activity of an antimicrobial to germs that were inconsistently sensitive or resistant to the antimicrobial).
  • Reducing the administered dose (A /) of an antimicrobial is of interest not only from the point of view of the treatment of microbial infections in humans or animals, in particular the reduction of side effects, but also, and this is not negligible, from an environmental point of view (decreased occurrence of resistance to antimicrobials).
  • the use of known antimicrobials at lower doses may help in the fight against the emergence of new resistance mechanisms.
  • the antimicrobial can be used at a reduced dose, wherein the antimicrobial dose administered corresponds to 1/50 to 3/4 of the antimicrobial dose required in the absence of co-administration of a compound according to the invention. invention for administration to a subject (man, animal) for treating microbial infections.
  • Increasing the effect of a constant-dose antimicrobial is of quantitative clinical interest by improving the kinetics of an antimicrobial and qualitative effect by making it possible to treat a patient (human or animal) suffering from microbial infection with an antimicrobial for which the strain was sensitive or inconsistently sensitive in the absence of potentiation.
  • Increasing the speed of the ⁇ antimicrobial effect reduces the time spent in the "infective" state by the patient or animal, thus reducing the epidemiology of the disease as well as the appearance and spread resistances.
  • the compounds according to the invention Thanks to the presence of the compounds according to the invention, it is possible to increase the bactericidal rate of antimicrobial antimicrobial antimicrobial constant dose. Thus, the rate of action of a potentiated antimicrobial can be increased. This is especially true for concentration-dependent antimicrobials.
  • the antimicrobial spectrum can be broadened, in particular at a constant dose of antimicrobial agent.
  • an antimicrobial potentiated by the compounds according to the invention can be used on strains on which it is no longer sensitive in the absence of potentiation (in particular because of the appearance of resistances).
  • the compound of formula (I) is sufficient to potentiate ⁇ antimicrobial, with the consequence that the use of a single compound of formula (I) is sufficient to potentiate ⁇ antimicrobial.
  • a combined use of inactive compounds may be considered. This is especially true when broad spectrum activity is sought.
  • it may be useful to co-administer a compound according to the invention which is particularly potentiating on Gram + bacteria and a compound according to the invention which is particularly potentiating on Gram - bacteria.
  • the phenylpropanes comprise a C 6 aryl skeleton substituted with at least one aliphatic:
  • the C 6 aryl backbone may comprise one or more substituents.
  • the compounds according to the invention advantageously have a number of carbon atoms ranging from 10 to 18, more preferably from 10 to 15.
  • the compounds according to the invention advantageously have a molecular weight of less than 350 g / mol, advantageously less than 300 g / mol, more advantageously of between 120 g / mol and 280 g / mol.
  • the most preferred compounds are purely hydrocarbon (as carbon and hydrogen atoms) or when they comprise oxygen atoms, the oxygen is preferably in the form of an ester or an ether.
  • the compounds advantageously have a LogP value which is greater than 2, more preferably between 2 and 5.
  • the compounds advantageously have low solubility in water.
  • the solubility in water is advantageously less than 500 mg / l, more preferably between 0.001 mg / l and 50 mg / l, more advantageously between 0.001 and 20 mg / l.
  • the compound according to the invention may advantageously form 0 to 1 hydrogen bond, more preferably 0 hydrogen bond.
  • the compound has the following formula (Ia):
  • Ri represents H or an alkyl radical Ci-C 6 alkenyl or C 2 -C 6
  • R 2 represents H or OH, 0-CO- (C 1 -C 4) alkyl, 0- (C 1 -C 4) alkyl-C 6, N-alkyl (Ci-C 6 ) 2 , advantageously R 2 represents H
  • R 3 represents H or an OH, O-CO- (C 1 -C 4 alkyl), O- (C 1 -C 4 ) alkyl radical, advantageously R 3 represents H
  • R 2 and R 3 may together form the corresponding lactone
  • R 5 represents an OH, O-C 1 -C 6 alkyl, O- (C 1 -C 4 ) alkyl-P enyl, O-C 2 -C 6 alkenyl radical, advantageously an O-C 1 -C 6 alkyl radical; C 6 , 0- (C 1 -C 4 ) alkylphenyl, O-C 2 -C 6 alkenyl,
  • R 4 is H or an alkyl radical C o -C 6
  • R 5 is an O-alkyl radical in C 2 -C 6 alkyl, 0- (C 1 -C 4 alkyl) - phenyl, 0- (alkenyl C 2 -C 4 alkyl) -phenyl, alkyl-C 6 o R 5 is H provided that R 4 represents an alkyl radical in C 2 -C 6, or R 2 represents an alkyl radical in C 2 -C 6, NOT-
  • R 5 represents OH with the proviso that R 2 represents a C 1 -C 6 alkyl radical
  • R 5 is O-alkyl, C 2 -C 6 alkyl, 0- (C 4 -C alkyl) -p enyl, alkyl-C 6.
  • n 0 or 1
  • Ri represents H or an alkyl radical Ci-C 6 alkenyl or C 2 -C 6
  • R 2 represents H or OH, 0-CO- (C 1 -C 4) alkyl, 0- (C 1 -C 4) alkyl-C 6, N-alkyl (Ci-C 6 ) 2 , advantageously R 2 represents H
  • R 3 represents H or an OH, O-CO- (C 1 -C 4 alkyl), O- (C 1 -C 4 ) alkyl radical, advantageously R 3 represents H
  • R 2 and R 3 may together form the corresponding lactone
  • R 5 represents an OH, O-C 1 -C 6 alkyl, O- (C 1 -C 4 ) alkyl-P enyl, O-C 2 -C 6 alkenyl radical, advantageously an O-C 1 -C 6 alkyl radical; C 6 , 0- (C 1 -C 4 alkyl) -p enyl, O-alkenyl
  • R 4 represents H or a C 3 -C 6 alkyl radical
  • R 5 represents an O-C 2 -C 6 , O- (C 1 -C 4 alkyl) phenyl radical
  • R 5 is H provided that R 4 represents an alkyl radical in C 3 -C 6, or R 2 represents an alkyl radical in C 2 -C 6 alkyl, N- (alkyl-C 6) 2
  • R 5 represents OH with the proviso that R 2 represents a C 3 -C 6 alkyl radical
  • R 5 represents an alkyl radical, C 2 -C 6 alkyl, 0- (C 4 -C alkyl) -p enyl.
  • n is 0.
  • R 5 preferably represents OH, O-C 1 -C 3 alkyl, 0- (alkyl Ci-C 2) -phenyl.
  • R 1 advantageously represents H or a C 1 -C 4 alkyl or C 2 -C 4 alkenyl radical.
  • R 2 advantageously represents H or an OH, O- (C 1 -C 4 alkyl) radical.
  • R3 advantageously represents H.
  • the preferred compounds according to the invention are benzoic acid, methyl salicylate or benzyl benzoate.
  • the compound has the following formula (Ib):
  • Ri represents H or an alkyl radical Ci-C 6 alkenyl or C 2 -C 6
  • R 2 represents H or OH, 0-CO- (C 1 -C 4) alkyl, 0- (C 1 -C 4) alkyl-C 6, N-alkyl (Ci-C 6 ) 2 , advantageously R 2 represents H R 3 represents H or an OH, O-CO- (C 1 -C 4 alkyl), O- (C 1 -C 4 alkyl), O- (C 2 -C 4 ) alkenyl radical, advantageously R 3 represents H
  • R 2 and R 3 may together form the corresponding lactone
  • Z represents a CH 2 -O-CO- (C 1 -C 6 ) alkyl radical
  • R 1 advantageously represents H.
  • R 2 advantageously represents H.
  • R 3 advantageously represents H.
  • Z preferably represents a CH 2 -O-CO- (C 1 -C 4) alkyl radical.
  • the preferred compounds according to the invention are cinnamyl acetate and trans-cinnamyl propionate.
  • the microbial infection is advantageously an infection induced by a pathogen selected from the following potentially pathogenic genera: Acetobacter, Acetobacterium, Acinetobacter, Citrobacter, Enterobacter, Enterococcus, Escherichia, Helicobacter, Klebsiella, Proteus, Providencia, Pseudomonas, Salmonella, Serratia, Staphylococcus, Streptococcus, Actinobacillus, Neisseria, Mannheima, Pasteurella, Candida, Aspergillus, Cryptococcus, Trichosporon, Malassezia, and Mycobacterium.
  • a pathogen selected from the following potentially pathogenic genera: Acetobacter, Acetobacterium, Acinetobacter, Citrobacter, Enterobacter, Enterococcus, Escherichia, Helicobacter, Klebsiella, Proteus, Providencia, Pseudomonas, Salmonella, Serratia, Staphylococcus, Strepto
  • the strain or bacterial species is advantageously chosen from the group consisting of: Acetobacter, Acetobacterium, Acinetobacter, Actinobacillus, Citrobacter, Enterobacter, Enterococcus, Escherichia, Helicobacter, Klebsiella, Mannheima, Pasteurella, Proteus, Providencia, Pseudomonas, Salmonella, Serratia, Staphylococcus, and Streptococcus.
  • the strain or bacterial species is advantageously chosen from the group consisting of Citrobacter freundii, Enterobacter aerogenes, Enterobacter cloacae, Escherichia coli, Klebsiella oxytoca, Klebsiella pneumoniae, Proteus mirabilis, Providencia stuartii, Salmonella sp, Serratia marcescens, Acinetobacter baumannii, Burkholderia cepacia, Pseudomonas aeruginosa, Staphylococcaceae, Staphylococcus aureus, Enterococcus faecium, and Enterococcus sp.
  • the bacterium can be either a gram bacterium or a gram + bacterium.
  • the bacterium is more preferably selected from the group consisting of
  • the fungus is advantageously chosen from the group consisting of: Candida, Aspergillus, Cryptococcus, Trichosporus. The fungus is more advantageously candida albicans.
  • the antimicrobial agent may be an antibiotic and / or antifungal agent.
  • the compound of formula (I) and antimicrobial F do not belong to the same family of chemical compounds.
  • the compound of formula (I) being derived from a terpenoid, ⁇ antimicrobial is not a terpenoid, or even is not an essential oil extract or a phenylpropanoid.
  • Membrane-active antibiotics especially beta-lactams, penicillins, cephalosporins, glycopeptides, fosfomycin, polymixins, bacitracin, cycloserine;
  • Antibiotics inhibiting the synthesis of proteins in particular aminoglycosides, tetracyclines, fusidic acid, chloramphenicol and its derivatives, macrolides, lincosamides, streptogramins, synergistines and oxazolidinones;
  • Antibiotics inhibiting the synthesis of nucleic acids, in particular quinolones, nitrofurans, ansamycins and fucidic acid;
  • Antibiotics inhibiting folate synthesis, especially sulfonamides and sulfonamide combinations
  • Antibiotics inhibiting the synthesis of mycolic acids in particular isoniazid, prothionamide, ethionamuide, pyrazynamide
  • the antibiotic is chosen from: antibiotics inhibiting peptidoglycan synthesis, antibiotics inhibiting the synthesis of nucleic acids, antibiotics inhibiting folate synthesis, antibiotics inhibiting the synthesis of mycolic acids, any of their pharmaceutically acceptable salts, and any combination thereof.
  • the particularly advantageous class of antibiotic is that of antibiotics inhibiting the synthesis of peptidoglycan.
  • the antibiotic is chosen from: amoxicillin, amoxicillin / clavulanic acid, imipenem, vancomycin, erythromycin, azithromycin, gentamicin, amikacin, colistin, clindamycin, ciprofloxacin, tigecycline.
  • the microbial infection is a bacterial strain induced by a bacterial strain, of the cocci type or gram-positive bacilli, and the antimicrobial agent is amoxicillin.
  • arnoxicillin is dosed at 1000 mg / dose and the cineole is dosed at 1000 mg / dose, advantageously 500 mg / dose, and still more advantageously at 250 mg / dose.
  • the microbial infection is a bacterial infection induced by a bacterial strain of E. coli or methicillin-resistant S. aureus type and the antimicrobial F is an amoxicillin / clavulanic acid mixture.
  • the ratio of amoxicillin / clavulanic acid: cineole is 10: 1, 1: 1 or 1: 5
  • the microbial infection is a bacterial infection induced by an Enterobacteriaceae, Pseudomonas or S. aureus strain and F antimicrobial is Ciprofloxacin.
  • Antifungals acting on microtubules in particular griseofulvin
  • the antifungal is advantageously chosen from polyenes, azoles, allylamines, thiocarbamates, echinocandins, griseofulvin, and fluorocytosine.
  • the microbial infection is a vaginal yeast infection and the antibiotic is sertaconozole.
  • the compounds according to the invention are advantageously administered systemically.
  • the compounds according to the invention can be used in any pharmaceutical composition formulated to facilitate its administration.
  • the pharmaceutical composition can include any pharmaceutically acceptable excipients commonly used such as vehicle (s) or diluent (s).
  • the pharmaceutical composition may be administered orally, enterally, parenterally (intravenously, intramuscularly or subcutaneously, intraperitoneally), transcutaneously (or transdermally or percutaneously), cutaneous, mucosal, (in particular transmucosal-oral, nasal, ophthalmic, otological, vaginal, rectal), intragastric, intracardiac, intraperitoneal, intrapulmonary or intratracheal.
  • the pharmaceutical composition may be in dry form, dry form to be reconstituted at the time of use (powder, lyophilisate, etc.), solid (in particular cachet, powder, capsule, pill, granule, suppository, tablet, and more precisely accelerated release tablet, gastro-resistant tablet or extended-release tablet), pasty substance (in particular gel, ointment, cream or ovum), liquid (in particular syrup, solution for injection, infusible or drinkable or eye drops), in the form of an aerosol ( spray, steam or gas), in the form of a patch, in injectable form (in an aqueous, non-aqueous or isotonic solution)
  • the pharmaceutical composition can be packaged for administration in the form of a single dose (single dose) or multiple dose (multidose).
  • the antimicrobial (s) and the compound (s) according to the invention may be administered in the same pharmaceutical composition or in separate pharmaceutical compositions, simultaneously, sequentially or spread over time.
  • the forms of the pharmaceutical compositions may be similar or distinct; the routes of administration may be identical or different.
  • the administration scheme will be adapted by the practitioner according to the case.
  • the routes of administration and dosages vary depending on a variety of parameters, for example depending on the condition of the patient, the type of infection and the severity of the infection to be treated or the antimicrobial used.
  • the animal is preferably a mammal, especially humans, pets, livestock.
  • the following examples illustrate the invention.
  • the minimum inhibitory concentration measurement tests are carried out in solid agar medium according to the international standards in force (CLSI standards), according to the protocol defined above.
  • the compounds and compositions incorporated in the agar may be first diluted in one or more solvents (Tween® 80 diluted in water -3.4 ml of Tween for 9.6 ml of water-, tween® 80 diluted in the propylene 10 - 3.4 ml of Tween for 9.6 ml of propylene-, or DMSO diluted in water).
  • Gain MIC 50 (MIC of the antibiotic alone) / (MIC50 (antibiotic + booster))
  • Gain MIC 90 (MIC90 of the antibiotic alone) / (MIC90 (antibiotic + booster))
  • the booster is a generic term for the potentiating compounds of the invention, of formula (I).
  • strains tested are isolated from various human samples (blood, urine, pulmonary aspirations, etc.).
  • Phenotypic characterization ESBL, wild, penicillinase,
  • Pseudomonas Genotypic characterization: ESBL, cephalosporinase, penicillinase, aeruginosa absence of porin, multiresistance, wild
  • Phenotypic characterization resistance to methicillin
  • Staphylococcus fluoroquinolone Staphylococcus fluoroquinolone, kanamicin, tobramicin, multiresistance, wild
  • Phenotypic characterization resistance to erythromycin, at
  • 64/500 corresponds to 1 for 8 or so (noted for 8)
  • 64/100 corresponds to 1 for about 1.5 (noted for 1.5)
  • - 64/50 corresponds to 1 for about 0.75 (noted for 0.75)
  • 64/10 corresponds to 1 for about 0.15 (noted for 0.15)
  • the potentiating effect of antibiotics was tested with benzyl benzoate and cinnamyl acetate.
  • the ratios shown in the tables are mass ratios.
  • the products are tested in successive dilution of 1% to 0.00375%.
  • the value> 1% indicates that no bacterial inhibition was observed at the concentrations tested.
  • a value equal to 1.00% corresponds to 10 000 mg / L (ie 10 g / L).
  • the test shows that the products are inactive (MIC> 10,000mg / l) in the majority of the solvents tested.
  • the test shows that potentiators potentiate amoxicillin on staphylococci at low doses (the MIC of the amox alone is between 0.25 and 32 mg / l).
  • potentiators potentiate ciprofloxacin at low doses (the MIC of gentamycin alone is between 0.125 and 8 mg / l).
  • the test shows that the potentiators potentiate the sertaconazole whereas the MIC 50 and the MIC 90 of the potentiators is equal to 1% on the candidates. This potentiation occurs at low doses (the MIC of sertaconazole alone is between 0.06 and 16 mg / l). This test also shows that, surprisingly, sertaconazole is not potentiated at high dose of potentiator whereas at low dose of these, it is potentiated.
  • the MIC of the antibiotic alone, or in combination with cinnamyl acetate or benzyl benzoate is measured at three different concentrations (lmg / L, 4mg / L, 16mg / L) in different solvents (Tween®80 or DMSO )
  • the control corresponds to the test carried out without cineole.
  • a control is made in each solvent tested: distilled water, Tween / water and DMSO.
  • DMSO control antibiotic alone in DMSO
  • the indication "> 64” means that the MIC is not measurable because greater than 64 mg / L, the indication “ ⁇ ” means that there is no visible culture in the e-test.
  • control ED 6 0.125 6 1.5 0.19 0.094 1 control Tween 4 0.125 6 1.5 0.25 0.19 0.5 water
  • benzyl benzoate or cinnamyl acetate also makes it possible to reduce the appearance of resistant bacteria.
  • benzyl benzoate or cinnamyl acetate have a MIC above 10,000 mg / L on these strains.
  • Ciprofloxacme DMSO addition of Ciprofloxacme in DMSO
  • the growth tests are made in a liquid medium with a dispersion of the antibiotic booster beforehand in a suitable solvent (tween / water).
  • the growth kinetics of the bacteria are measured in the presence of Augmentin®, Augmentin® boosted cinnamyl acetate (AC) / benzyl benzoate (BB) or cinnamyl acetate / benzyl benzoate.
  • Augmentin® Augmentin® boosted cinnamyl acetate (AC) / benzyl benzoate (BB) or cinnamyl acetate / benzyl benzoate.
  • AC Augmentin® boosted cinnamyl acetate
  • BB benzyl benzoate
  • cinnamyl acetate / benzyl benzoate When used alone, benzyl benzoate or cinnamyl acetate have a MIC above 10,000 mg / L on these strains.
  • 99/1 represents a mass ratio of 64/100
  • 4XCMI means that the antibiotic concentration is 4 times higher than its MIC, measured when used alone on the strain in question.
  • Augmentin 64/100 AC 4XCMI means that the Augmentin® concentration is 4 times its MIC (alone) and the Augmentin® / test compound mass ratio is 64/100.
  • witness bacteria alone
  • mice Balb / c mice, the antimicrobial product or the antimicrobial + booster mixture, are injected (se).
  • the doses administered are as follows:
  • Augmentin® Group 1 (AMC) 30 mg / kg
  • mice are euthanized, and the blood collected, heparinized and centrifuged to extract the plasma.
  • the ratio of the plasma concentration relative to the MIC is obtained by the successive dilutions of the plasma. Although this method is semi-quantitative, it nevertheless shows that the effect is more intense when benzyl benzoate is present (higher AUC). Similarly, and unambiguously, the addition of benzyl benzoate allows to extend the time spent above the MIC.

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