Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D241/00—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings
  • C07D241/36—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings condensed with carbocyclic rings or ring systems
  • C07D241/38—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings condensed with carbocyclic rings or ring systems with only hydrogen or carbon atoms directly attached to the ring nitrogen atoms
  • C07D241/46—Phenazines
• • C—CHEMISTRY; METALLURGY
  • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
  • C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
  • C12Q1/00—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions
  • C12Q1/02—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions involving viable microorganisms
  • C12Q1/18—Testing for antimicrobial activity of a material
• • G—PHYSICS
  • G01—MEASURING; TESTING
  • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
  • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
  • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
  • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
  • G01N33/53—Immunoassay; Biospecific binding assay; Materials therefor
  • G01N33/531—Production of immunochemical test materials
  • G01N33/532—Production of labelled immunochemicals
  • G01N33/533—Production of labelled immunochemicals with fluorescent label
• • G—PHYSICS
  • G01—MEASURING; TESTING
  • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
  • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
  • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
  • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
  • G01N33/53—Immunoassay; Biospecific binding assay; Materials therefor
  • G01N33/543—Immunoassay; Biospecific binding assay; Materials therefor with an insoluble carrier for immobilising immunochemicals
  • G01N33/54353—Immunoassay; Biospecific binding assay; Materials therefor with an insoluble carrier for immobilising immunochemicals with ligand attached to the carrier via a chemical coupling agent

Definitions

• the invention relates to cyclic compounds, and in particular their use in the measurement of bacterial efflux.
• efflux is a mechanism by which cells reject compounds that are toxic for their metabolism, such as antibiotics, heavy metals, drugs, etc., into the external environment.
• Efflux is an active, energy-dependent transport mechanism provided by transmembrane proteins called efflux pumps.
• One of the aims of the invention is to provide compounds and methods for measuring bacterial efflux.
• Another object of the invention consists in proposing a method making it possible to evaluate the antibiotic resistance of bacteria.
• X - is a halogen atom, or an acceptable counter ion, in particular Cl,
• n being an integer varying from 1 to 3
• i being an integer varying from 1 to 3 and where n+i varies from 1 to 4;
• R1 is -C 4 H 7 and R2 is C 8 H 17 , and
• R3 is a -CH 3 , or a C2-C8 alkyl, said C2-C8 alkyl possibly being substituted by one or more heteroatoms;
• X- is a halogen atom, or an acceptable counter ion, in particular Cl,
• R1 is a Cn+i alkyl
• R2 is a Cn alkyl
• R1 is a Cn alkyl
• R2 is a Cn+i alkyl
• n being an integer varying from 1 to 3
• i being an integer varying from 1 to 3 and where n+i varies from 2 to 4;
• R1 is C 4 H 9 and R2 is C 8 H 17 , and
• R3 is -CH3, or C2-C8 alkyl, said C2-C8 alkyl possibly being substituted by one or more heteroatoms;
• X - is a halogen atom, or an acceptable counter ion, in particular Cl,
• n being an integer varying from 1 to 3
• i being an integer varying from 1 to 3 and where n+i varies from 1 to 4;
• R3 is a -CH 3 , or a C2-C8 alkyl, said C2-C8 alkyl possibly being substituted by one or more heteroatoms;
• the invention is based on the surprising observation made by the inventors that the aforementioned compounds of formula I are colored and fluorescent compounds which are effectively effluxed by bacteria by means of the various efflux pumps, so that said compounds make it possible to measure bacterial efflux and to measure a potential resistance of said bacteria.
• the compounds of formula I are phenaziniums, i.e. cationic protonated forms of phenazines. Alkylated forms of the phenaziniums of the invention are also contemplated.
• X ⁇ is an acceptable and in particular pharmaceutically acceptable counter-anion, that is to say a counter-anion the use of which is compatible with animal or bacterial physiology.
• Advantageous counter-anions are in particular counter-anions where X is a halogen atom such as F, Cl, Br or even I, the advantageous halogen being Cl. hexafluorophosphate (PF 6 - ) or even tetrafluoroborate (BF 4 - ).
• R1 and R2 are -CH 3 or -C 4 H 9 groups
• R1 and R2 are C1-C4 alkyls, i.e. C1, C2, C3 or C4 alkyls, preferably linear, such that R1 and R2 always have a difference carbon atom.
• This is defined by the phase specifying that if R1 is Cn alkyl, R2 is a Cn+i alkyl, and if R1 is Cn+i alkyl, R2 is a Cn alkyl, where i being an integer ranging from 1 to 3 and where n+i varies from 2 to 4,
• R1 is -C 4 H 7 and R2 is C 8 H 17 .
• R1 and R2 are identical to each other words.
• R1 and R2 are linear C1-C4 alkyls
• R1 or R3 are C3 alkyls, they can be -C 3 H 7 (i.e. -CH 2 -CH 2 -CH3) or -CH(CH 3 ) 2 , and when they are C4 alkyls they can be -C 4 H 9 (i.e. -CH 2 -CH 2 -CH 2 -CH 3 ), -CH(CH 3 )-CH 2 -CH 3 or -CH 2 -CH(CH 3 ) 2 or -C(CH 3 ) 3 .
• this is a methyl (-CH 3 ) or a C2-C8 alkyl, i.e. an alkyl:
• each of the carbon atoms can be substituted by a heteroatom, i.e. by an oxygen (O), nitrogen (N) or sulfur (S) atom, or even phosphorus (P).
• a C4 alkyl can have one of its carbons substituted by an oxygen, and one will obtain the following R3 residues:
• the invention relates to the compound as defined above, where R1 and R2 are each a C2-C4 alkyl, such as:
• R1 is a Cn+i alkyl
• R2 is a Cn alkyl
• R2 is a Cn+i alkyl
• R1 is a Cn alkyl
• n varying from 1 to 3
• i being an integer varying from 1 to 3 and where n+i varies from 1 to 4
• R3 is as defined below.
• the invention relates to the compound as defined above, where R3 is a C2-C4 alkoxy group, in particular methoxyethyl, a dimethylamineethyl or methylaminexethyl group.
• the invention relates to the aforementioned compound, said compound being chosen from the group of compounds of formula I, where R1, R2 and R3 are together as indicated in each row of the following table:
• the invention relates to the aforementioned compound, said compound being chosen from the compounds of formulas 47, 52, 53, 392 and 29 following: (47), (52), and (53), (392), and (29).
• the invention relates to the compound as defined above, as a medicament, or for its use as a medicament. It is also envisaged a use of the compound as defined above, for the manufacture of a medicament.
• a pharmaceutical composition comprising, as active substance, a compound as defined above, in association with a pharmaceutically acceptable vehicle.
• the compound of formula (I) as defined above, or its pharmaceutically acceptable salt is administered or can be administered in a unit dose, or is packaged in a unit dose, of approximately 50 mg to approximately 1500 mg, in particular of approximately 150 to approximately 200 mg.
• the compound of formula (I) as defined above, or its pharmaceutically acceptable salt is administered or can be administered with a dosage regimen of 50 mg/d to approximately 1500 mg/d, in particular from approximately 150 mg/d to approximately 200 mg/d.
• the compound of formula (I) as defined above, or its salt pharmaceutically is administered or can be administered in a form suitable for administration by the oral or injectable route. More preferably, the compound of formula (I) as defined above, or its pharmaceutically acceptable salt, is administered or administrable in the form of a powder, cachets, capsules or sachets.
• the aforementioned compound or the aforementioned pharmaceutical composition is used within the framework of the treatment, or for the treatment of infections with Gram positive bacteria.
• the aforementioned compound has antibacterial properties that may prove useful in the treatment of infections.
• the aforementioned compound is used in the context of antibacterial therapies, to treat pathologies or infections linked to contamination by Gram-positive bacteria which are not able to efflux compounds, or bacteria which do not express or little pumps responsible for resistance to antibiotics.
• the aforementioned compound which has antibiotic properties, or at least antibacterial properties, can be used in the context of the decontamination of inert surfaces infected, or contaminated by bacteria.
• the compound is then brought into contact with the contaminated surface in order to kill and/or inhibit the growth of contaminating bacteria.
• the compound can be used in the form of a powder to be distributed on the surface to be decontaminated, or in the form of a solution which can be poured or sprayed on the surface to be decontaminated.
• Gram-positive bacteria and more particularly Gram-positive bacteria which are not capable of effluxing compounds, that is to say bacteria which do not express or little pumps responsible for multiple drug resistance (pumps allowing efflux).
• the invention also relates to the use of a compound as defined above, for evaluating or measuring, that is to say for qualitatively observing or quantifying the efflux of said compound by a bacterium.
• the compound according to the invention is capable of being expelled from bacteria by the efflux mechanism. Also, insofar as the compound according to the invention is colored and/or fluorescent, it is easy to follow its efflux from the inside of the bacterium to the outside.
• the compound of the invention it is also possible to use the compound of the invention to identify whether or not a bacterial isolate overproduces its efflux pumps. Also, by measuring or evaluating the efflux of the compound of the invention, it is possible to determine whether a pump is overproduced or overexpressed, or on the contrary underproduced or underexpressed.
• the compound is colored and/or fluorescent, it will be possible to measure on the one hand the coloration/fluorescence at the start of the experiment when bringing the compound into contact with the bacteria, and after a determined time, either the fluorescence or the color in the bacteria, or in the external medium.
• the invention relates to the aforementioned use, for evaluating or measuring the efflux by Gram-positive bacteria.
• the msrA and msrB genes are responsible for an MS-type resistance phenotype, that is to say an inducible resistance to macrolides whose nucleus comprises 14 and 15 carbons (C14 and C15) and to compound B of streptogramins, after induction by erythromycin.
• the mef gene causes a resistance phenotype called M, characterized by a limited resistance to C14 and C15 macrolides.
• vga A , vgaB genes encode efflux proteins of the only compound A of the synergistins. All these genes are found in different species of Staphylococcus aureus (SA) and coagulase negative staphylococci (CNS).
• SA Staphylococcus aureus
• CNS coagulase negative staphylococci
• the invention relates to the aforementioned use, for evaluating or measuring the efflux by Gram-negative bacteria.
• the aforementioned use relates to the measurement or evaluation
• the invention relates to a kit, or kit, for detecting or measuring bacterial efflux, comprising
• the kit of the invention therefore contains a compound according to the invention which is capable of being effluxed by bacteria, and in addition a control of the experiment, a control bacterium for which the efflux of said compound is known.
• This control bacterium can express either a wild-type pump, and whose efflux is known in particular with precision and in a reproducible manner, or a mutant pump which no longer allows efflux due to a lack of expression of the proteins forming the pump or a structural modification affecting the function.
• Other control bacteria can obviously be used and in an advantageous aspect it can be supplied with the kit, or the kit, both a positive control (a bacterium with a functional efflux pump) and a negative control (a bacterium with a non-functional or absent efflux pump).
• the compound according to the invention is colored and/or fluorescent
• color palettes making it possible to define whether or not a bacterium is capable of effluxing a compound, or alternatively means for detecting fluorescence.
• the invention relates to the use of the kit as defined above, for measuring or quantifying the efflux of said compound by a bacterium, in particular a Gram-positive bacterium, in particular S. aureus , B. subtilis , and S. pneumoniae .
• a bacterium in particular a Gram-positive bacterium, in particular S. aureus , B. subtilis , and S. pneumoniae .
• the invention relates to the use of the kit as defined above, for measuring or quantifying the efflux of said compound by a Gram-negative bacterium, in particular Escherichia coli .
• the invention relates to the aforementioned kit, further comprising a protonophore, in particular chosen from 2,4-dinitrophenol, carbonyl cyanide-p-trifluoromethoxyphenylhydrazone (FCCP), carbonyl cyanide m-chlorophenyl hydrazone (CCCP), C4R1, Ellipticine, 10-[2-(3-hydroxy-6-oxo-xanthen-9-yl)benzoyl]oxidecyl-tri phenyl-phosphonium bromide and 2-(2-Hydroxyaryl)hexylphosphonium bromide, and in particular CCCP.
• a protonophore in particular chosen from 2,4-dinitrophenol, carbonyl cyanide-p-trifluoromethoxyphenylhydrazone (FCCP), carbonyl cyanide m-chlorophenyl hydrazone (CCCP), C4R1, Ellipticine, 10-[2-(3-hydroxy-6-ox
• a protonophore in particular CCCP, is particularly appropriate.
• the protonophore found in the aforementioned kit is intended to be used at concentrations varying from 0.25 to 15 ⁇ g.mL -1 .
• the invention relates to the use of a compound as defined above, to assess the resistance of a bacterium to a bacteriostatic or bactericidal compound.
• the compound according to the invention can be effluxed by bacterial pumps, the latter can therefore logically be used to evaluate the effectiveness of the efflux of bacteria.
• the invention relates to a method for evaluating resistance, in particular resistance due to an efflux mechanism, of a bacterium to a bacteriostatic or bactericidal compound, comprising:
• the pellet of bacteria has the color of a pellet of bacteria from a culture of untreated bacteria, said bacterium is resistant to said bacteriostatic or bactericidal compound, and
• the pellet of bacteria has a color different from the color of a pellet of bacteria from the culture of untreated bacteria, said bacterium is not resistant to said bacteriostatic or bactericidal compound.
• the evaluation method may include a filtration step replacing the centrifugation step.
• the bacteria culture is passed over a filter and the bacteria settle on the latter.
• the coloring of the solid deposit of bacteria present on the filter is then evaluated to determine whether said bacteria exhibit resistance, in particular due to an efflux mechanism, to a bacteriostatic or bactericidal compound.
• the invention thus relates to a method for evaluating the resistance, in particular a resistance due to an efflux mechanism, of a bacterium to a bacteriostatic or bactericidal compound, comprising:
• the solid deposit on the filter has the same color as a solid deposit from a culture of untreated bacteria, said bacterium is resistant to said bacteriostatic or bactericidal compound, and
• the solid deposit has a color different from the color of a solid deposit resulting from the culture of untreated bacteria, said bacterium is not resistant to said bacteriostatic or bactericidal compound.
• the invention relates to a method for evaluating resistance due to an efflux mechanism of a bacterium to a bacteriostatic or bactericidal compound, comprising:
• the pellet of bacteria has the color of a pellet of bacteria from the culture of untreated bacteria, said bacterium is resistant to said bacteriostatic or bactericidal compound, by efflux of said bacteriostatic or bactericidal compound, and
• said bacterium is not resistant to said bacteriostatic or bactericidal compound by efflux of said bacteriostatic or bactericidal compound.
• the invention relates to the aforementioned method, said method further comprising a step of incubating the culture of bacteria with a protonophore.
• the invention relates to a method for evaluating resistance due to an efflux mechanism of a bacterium to a bacteriostatic or bactericidal compound, comprising:
• the pellet of bacteria has the color of a pellet of bacteria from a culture of untreated bacteria, said bacterium is resistant to said bacteriostatic or bactericidal compound, by efflux of said bacteriostatic or bactericidal compound, and
• said bacterium is not resistant to said bacteriostatic or bactericidal compound by efflux of said bacteriostatic or bactericidal compound.
• This method with a pretreatment is particularly advantageous in the context of measuring the efflux of Gram-negative bacteria.
• the aforementioned compound is very simple and is based on the color properties of the compounds according to the invention.
• the compound will be effluxed and released into the environment.
• the bacteria will have no more compounds and the bacterial pellet from the culture will have the color of a pellet that has not been treated with the colored compound.
• the compound Conversely, if the efflux pumps are not functional, the compound will accumulate in the bacteria, and the pellet will then take on a color which will be that (with one variation in intensity) of the colored compound.
• the colorimetric tests can be carried out using techniques known to those skilled in the art, and in particular according to the CIE 1976 L*a*b* chromatic space. It is a color space particularly used for the characterization of surface colors.
• Pellet A represents a pellet of strain CIP 76.26, a reference strain with normal efflux activity – the pellet is pale pink.
• Pellet B represents a pellet of the SA 1199 strain, a clinical strain with light to moderate efflux activity – the pellet is orange.
• Pellet C represents a pellet of strain SA 1199 B which corresponds to a mutant strain with high efflux activity – the pellet is white/off-white.
• Base D represents a base of strain SA K1758, a mutant strain with no efflux pump – the base is shiny dark pink.
• Pellet A represents a wild BmrA strain pellet – the pellet is pale pink.
• Pellet B represents a pellet of a strain overexpressing BmrA – the pellet is white.
• Pellet C represents a pellet of bacteria with a deletion of BmrA (BmrA ⁇ ) – the pellet is dark pink.
• D NorA deleted strain corresponding to SA K1758 fixed with PFA
• E wild type strain corresponding to CIP 76.25 fixed with ethanol
• F reference strain corresponding to the SA strain fixed with ethanol
• G NorA-overproducing strain corresponding to SA1199B fixed with ethanol
• H NorA-deleted strain corresponding to SA K1758 fixed with ethanol.
• the "9A” pellet represents a wild PatA-PatB strain pellet.
• Pellet “9B” represents a PatA/PatB overexpressing strain pellet.
• the “9C” pellet represents a PatA/PatB deletion strain pellet.
• Antibiotic efflux due to its polyspecificity, has long been identified as a complement to more traditional resistance mechanisms (target mutation, enzymes such as Beta-lactamase, etc.), but more recently, as intervening upstream of other mechanisms, favoring their selection.
• Example 2-1 Staphylococcus aureus
• Bacterial strains the inventors used the following strains of Staphylococcus aureus :
• Compound 053 (see synthesis in example 1) is prepared in pure DMSO (Sigma) at a concentration of 20 mg/mL. It will then be diluted in milliQ water to obtain a stock solution of 1000 ⁇ g/mL.
• Staining of the bacteria the bacteria in the exponential phase of growth are incubated for 15 min in the presence of compound 053. Then the bacteria are washed twice in phosphate buffer and centrifuged, the pellets are observed with the naked eye.
• Fluorescence measurement The bacteria in the exponential phase of growth are incubated for 15 min in the presence of compound 053. The optical density at 600 nm is then adjusted to 0.5 and 50 ⁇ l are transferred into a black microtiter plate. The fluorescence is read in a Tecan M200 microplate reader.
• the cell pellets are orange in color indicating moderate efflux activity, this is mainly due to the inherent yellow color of the cells.
• Figures 1-3 show the color difference (1A) and spectrofluorometric difference (1B) observed in different reference strains (strain A, CIP 76.25), a clinical strain (strain B, SA1199), and laboratory-constructed norA efflux pump mutants of strain B: overexpressing NorA (strain C, SA 1199B) and deleted NorA (strain D, SA K1758).
• strain C has an overexpressed efflux pump, the efflux of 053 is stronger, and the cell pellet appears white (053 is completely eliminated by efflux).
• strain D lacks an efflux pump, the cell pellet appears dark pink.
• Intermediate colors can be observed for reference strains (strain A) and clinical strains (strain B), suggesting mild to moderate activity.
• the spectrofluorimetric results ( ) show that compound 053 is fluorescent when accumulated in bacteria and that, like staining, fluorescence depends on the level of production of the NorA pump.
• the NorA pumpless mutant (SAK 1758) has high fluorescence at 670 nm ( Figures 2 and 3 , black curve and histogram).
• fluorescence requires a suitable spectrofluorimeter.
• the fluorescence measurement is quantitative and makes it possible to determine with precision the level of efflux activity of the isolates.
• the inventors also carried out a reading of the fluorescence by flow cytometry in order to validate the results previously obtained by spectrofluorimetry.
• flow cytometry only considers the fluorescence within the cell and not that surrounding it, thus making it possible to directly assess the concentration of compound 053 within the cell without the need for rinsing.
• Example 2-2 Bacillus subtilis
• Bacterial strains the inventors used
• Figures 4-6 show the color difference ( ) and the spectrofluorometric difference ( Figures 5 and 6) observed on the different strains of Bacillus subtilis .
• Strain A is wild-type B. subtilis 168 (DSM 402)
• strain B, BmrA+++ is a BmrA overexpressing mutant
• strain C is a BmrA deletion mutant (BmrA ⁇ ). Since strain B overexpresses the BmrA efflux pump, compound 053 is completely effluxed out of the cell, and the cell pellet appears white. On the other hand, for strain C which does not have an efflux pump, the cell pellet appears dark pink.
• Strain A is a normal wild type strain expressing normal efflux activity; compound 053 is therefore partially effluent and the cell pellet appears pale pink, suggesting mild to moderate activity. Similar activity is confirmed and quantified using fluorescence spectroscopy ( Figures 5 and 6).
• the wild-type strain (DSM 402) producing low levels of pumps exhibits intermediate levels of fluorescence ( Figures 5 and 6, curve and histogram).
• fluorescence requires a suitable spectrofluorimeter.
• the fluorescence measurement is quantitative and makes it possible to determine with precision the level of efflux activity of the isolates.
• the inventors compared the staining induced by compound 053 on different strains of Streptococcus pneumoniae bacteria: a wild strain ("WT”), a strain overexpressing PatA-PatB, an ABC transporter of Streptococcus pneumoniae allowing the transport of molecules outside the cell involved in the resistance of this pathogen to fluoroquinolone type antibiotics (“OVP”), and a strain deleted of PatA-PatB (“DEL").
• WT wild strain
• PatA-PatB an ABC transporter of Streptococcus pneumoniae allowing the transport of molecules outside the cell involved in the resistance of this pathogen to fluoroquinolone type antibiotics
• DEL strain deleted of PatA-PatB
• Bacterial strains the inventors used
• Figures 9 and 10 show the color difference ( ) and the spectrofluorometric difference ( ) observed on the different strains of Streptococcus pneumoniae.
• Compound 053 therefore makes it possible to qualitatively and quantitatively distinguish a strain overexpressing an ABC PatA-PatB transporter from a strain not overexpressing or not expressing this transporter at all.
• Example 2-4 Escherichia coli
• PBP potassium phosphate buffer
• Figures 11 to 16 show the color difference ( Figures 11 and 14) and the spectrofluorimetric difference ( Figures 12, 13, 15 and 16) observed on the different strains of Escherichia coli.
• Strain EC (ref) is the reference strain (ATCC 11775) showing normal efflux
• strain AG100 is the wild-type E. coli strain (Wild) also showing normal efflux
• strain AG102 is an AcrAB overexpressing mutant (acrAB+++) showing high efflux
• strain AG100A ( ⁇ acrAB) is an acrAB deletion mutant showing low efflux.
• CCCP Carbonyl Cyanide m-Chlorophenylhydrazone
• the experimental protocol is the same as that described in the examples except that the cells are treated for 1 hour with CCCP (5 ⁇ g/mL) in a phosphate buffer (PPB). After PCC treatment, the entire experiment is carried out in PPB instead of MH-II broth from step 4.

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• 2022
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