WO2001097791A2 - Utilisation d'acides en c4-c10 pour la prévention des infections a bactéries a gram négatif - Google Patents
Utilisation d'acides en c4-c10 pour la prévention des infections a bactéries a gram négatif Download PDFInfo
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- WO2001097791A2 WO2001097791A2 PCT/FR2001/001971 FR0101971W WO0197791A2 WO 2001097791 A2 WO2001097791 A2 WO 2001097791A2 FR 0101971 W FR0101971 W FR 0101971W WO 0197791 A2 WO0197791 A2 WO 0197791A2
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- Prior art keywords
- use according
- sodium
- radical
- salmonella
- formula
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- 239000002253 acid Substances 0.000 title abstract description 9
- 150000007513 acids Chemical class 0.000 title abstract description 6
- 208000027096 gram-negative bacterial infections Diseases 0.000 title abstract 2
- 241000607142 Salmonella Species 0.000 claims abstract description 38
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 15
- 150000003839 salts Chemical class 0.000 claims abstract description 7
- 150000002148 esters Chemical class 0.000 claims abstract description 6
- 229960005480 sodium caprylate Drugs 0.000 claims description 59
- BYKRNSHANADUFY-UHFFFAOYSA-M sodium octanoate Chemical compound [Na+].CCCCCCCC([O-])=O BYKRNSHANADUFY-UHFFFAOYSA-M 0.000 claims description 59
- 208000015181 infectious disease Diseases 0.000 claims description 42
- 241000894006 Bacteria Species 0.000 claims description 36
- WWZKQHOCKIZLMA-UHFFFAOYSA-N octanoic acid Chemical compound CCCCCCCC(O)=O WWZKQHOCKIZLMA-UHFFFAOYSA-N 0.000 claims description 28
- 239000003651 drinking water Substances 0.000 claims description 23
- 235000020188 drinking water Nutrition 0.000 claims description 23
- 150000001875 compounds Chemical class 0.000 claims description 22
- 241001465754 Metazoa Species 0.000 claims description 17
- 239000005635 Caprylic acid (CAS 124-07-2) Substances 0.000 claims description 12
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical group [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 12
- 229960002446 octanoic acid Drugs 0.000 claims description 12
- 230000007935 neutral effect Effects 0.000 claims description 11
- 206010039438 Salmonella Infections Diseases 0.000 claims description 10
- 206010039447 salmonellosis Diseases 0.000 claims description 10
- 125000004432 carbon atom Chemical group C* 0.000 claims description 7
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 6
- 238000002360 preparation method Methods 0.000 claims description 6
- 239000004480 active ingredient Substances 0.000 claims description 4
- 150000001340 alkali metals Chemical group 0.000 claims description 4
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 4
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 claims description 3
- FBUKVWPVBMHYJY-UHFFFAOYSA-N nonanoic acid Chemical class CCCCCCCCC(O)=O FBUKVWPVBMHYJY-UHFFFAOYSA-N 0.000 claims description 3
- 229910052708 sodium Inorganic materials 0.000 claims description 3
- 239000011734 sodium Substances 0.000 claims description 3
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 claims description 2
- 229910052783 alkali metal Inorganic materials 0.000 claims description 2
- 125000003118 aryl group Chemical group 0.000 claims description 2
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 2
- 229910052700 potassium Inorganic materials 0.000 claims description 2
- 239000011591 potassium Substances 0.000 claims description 2
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 2
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- WXMKPNITSTVMEF-UHFFFAOYSA-M sodium benzoate Chemical compound [Na+].[O-]C(=O)C1=CC=CC=C1 WXMKPNITSTVMEF-UHFFFAOYSA-M 0.000 description 41
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- DEFVIWRASFVYLL-UHFFFAOYSA-N ethylene glycol bis(2-aminoethyl)tetraacetic acid Chemical compound OC(=O)CN(CC(O)=O)CCOCCOCCN(CC(O)=O)CC(O)=O DEFVIWRASFVYLL-UHFFFAOYSA-N 0.000 description 4
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- GXVUZYLYWKWJIM-UHFFFAOYSA-N 2-(2-aminoethoxy)ethanamine Chemical compound NCCOCCN GXVUZYLYWKWJIM-UHFFFAOYSA-N 0.000 description 1
- WLJVXDMOQOGPHL-PPJXEINESA-N 2-phenylacetic acid Chemical compound O[14C](=O)CC1=CC=CC=C1 WLJVXDMOQOGPHL-PPJXEINESA-N 0.000 description 1
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- UQXNEWQGGVUVQA-UHFFFAOYSA-N 8-aminooctanoic acid Chemical class NCCCCCCCC(O)=O UQXNEWQGGVUVQA-UHFFFAOYSA-N 0.000 description 1
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- OYHQOLUKZRVURQ-HZJYTTRNSA-N Linoleic acid Chemical compound CCCCC\C=C/C\C=C/CCCCCCCC(O)=O OYHQOLUKZRVURQ-HZJYTTRNSA-N 0.000 description 1
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- ZQPPMHVWECSIRJ-KTKRTIGZSA-N oleic acid Chemical compound CCCCCCCC\C=C/CCCCCCCC(O)=O ZQPPMHVWECSIRJ-KTKRTIGZSA-N 0.000 description 1
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- PVGBHEUCHKGFQP-UHFFFAOYSA-N sodium;n-[5-amino-2-(4-aminophenyl)sulfonylphenyl]sulfonylacetamide Chemical compound [Na+].CC(=O)NS(=O)(=O)C1=CC(N)=CC=C1S(=O)(=O)C1=CC=C(N)C=C1 PVGBHEUCHKGFQP-UHFFFAOYSA-N 0.000 description 1
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Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
- A61K31/19—Carboxylic acids, e.g. valproic acid
- A61K31/20—Carboxylic acids, e.g. valproic acid having a carboxyl group bound to a chain of seven or more carbon atoms, e.g. stearic, palmitic, arachidic acids
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
- A61K31/19—Carboxylic acids, e.g. valproic acid
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
- A61K31/19—Carboxylic acids, e.g. valproic acid
- A61K31/192—Carboxylic acids, e.g. valproic acid having aromatic groups, e.g. sulindac, 2-aryl-propionic acids, ethacrynic acid
-
- 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
-
- 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 present invention relates to the use of C 4 -C ⁇ acids for the prevention of infections with Gram negative bacteria, in particular with Salmonella, both in animals and in humans.
- Salmonella are enteroinvasive bacteria pathogenic for humans and animals.
- iagA Transcription of iagA requires the production of two derepressants, SprA (or HilC or SirC) and HilD, which are encoded by SPI-1 genes and are part of the AraC / XylS family (Eichelberg et al., 1999, Mol. MicrobioL, 1999, 33, 139-152; Schechter et al., Mol. MicrobioL, 1999, 32, 629-642).
- the transcription of iagA is also controlled directly or indirectly by two two-component systems, RcsB-RcsC and PhoP-PhoQ, which are not coded by genes located at centisome 63.
- the RcsB-RcsC system responds to osmolarity (Arricau et al., Mol. MicrobioL, 1998, 29, 835-850) and the Phop-PhoQ system for the concentration of divalent cations such as calcium and magnesium ions (Garcia Véscoci et al., Cell, 1996, 84, 165- 174; Miller et al., Proc. Natl. Acad. Sci. USA, 1989, 86, 5054-5058) of the environmental medium.
- divalent cations such as calcium and magnesium ions
- the PhoP-PhoQ and RcsB-RcsC systems suppress directly or indirectly the expression of iagA.
- the genes coding for the components and targets of the Inv-Spa-Prg secretion apparatus are not expressed, the Salmonella are unable to enter the epithelial cells in culture.
- the PhoP-PhoQ and RcsB-RcsC systems no longer repress the expression of iagA.
- Sip proteins are also synthesized, but they remain stored in the cytoplasmic compartment because the secretion apparatus is inactive.
- the activity of the secretory apparatus will be triggered by contact with the epithelial cell (Galan, 1996).
- the Sip proteins will be secreted and form a translocator, which will be used to inject the effector proteins, including StpA and AvrA, into the cytosol of the target cell.
- These effector proteins then activate different signaling pathways, leading to a variety of cellular responses and ultimately the entry of Salmonella into the cell.
- these two conditions osmolarity and high concentration of divalent cations
- Salmonella is then very greatly reduced (Bajaj et al, Mol. MicrobioL, 1996, 22, 703-714). In fact, Salmonella cultured in a medium with low osmolarity or with a low concentration of divalent cations are incapable of penetrating into the epithelial cells in culture. All the data reported above shows that the expression of the entry phenotype in Salmonella is very finely controlled by regulators acting in cascade (all are probably not identified) depending on the environmental conditions. If one interferes with only one of these regulators, then this should result in a non-invasive phenotype.
- Salmonella therefore always constitutes a major public health problem.
- Epidemiological studies have clearly shown that this resurgence of salmonellosis (except in the case of typhoid fever, which is a strictly human disease) was due to the consumption of animal products contaminated with Salmonella.
- S. enteritidis which has caused a global epidemic.
- the source of contamination by S. enteritidis has been fully identified. These were eggs and egg products.
- lauric acid for example, which is a saturated fatty acid whose chain is formed by 12 carbon atoms, has bactericidal activity in vitro on S. typhi, Vibrio cholerae, and Shigella sonnei at a concentration of 0.25 g / 1.
- caprylic acid has no bacteriostatic or bactericidal effect on Gram-positive or Gram-negative bacteria, while other fatty acids with a more saturated carbon chain long, in particular from 12 carbon atoms such as lauric acid or certain unsaturated fatty acids such as for example linoleic acid and oleic acid, are very effective (Kabara et al., Antimicrob. Agents Chemother, 1972, 2, 23-31).
- fatty acids such as, for example, n-hexanoic, caprylic and decanoic acids exhibit, at acidic pH, bactericidal activity on a wide variety of Gram-positive or negative microorganisms and make it possible to treat different types of 'infections (US patents 4,489,097 and US 4,406,884, patent application EP 0 021 504). These documents specify however that to be effective, these acids must be used at acidic pH to be in the form of free acid.
- bacteriostatic or bactericidal activity of fatty acids is linked to the length of the carbon chain and to the number of unsaturations which it carries, the most important activity being attributed to fatty acids containing at least 12 atoms of carbon and preferably one or two unsaturations.
- a subject of the present invention is therefore the use of an effective amount of at least one compound of formula (I) below:
- R, -COO-R 2 in which: - Ri represents a saturated C 4 -C carbon chain, optionally substituted by one or more hydroxyl or amino functions or by an aromatic ring; - R represents a hydrogen atom; a monovalent alkali metal atom; an alkyl radical; it being understood that when R represents a hydrogen atom and that Ri represents a saturated C 7 carbon chain substituted by an a ine function, then said amine function is not in position 2 or 8; as active ingredient, for the preparation of a pharmaceutical composition having a neutral pH intended to prevent infections with Gram-negative bacteria, in humans or in animals.
- active principle for the preparation of a pharmaceutical composition having a neutral pH intended to prevent infections with Gram negative bacteria and in particular with Salmonella, both in humans and in animals.
- the compounds of formula (I) above can therefore be in the form of an acid, a salt or an ester.
- the inventors have in particular demonstrated that the preventive administration of a composition having a neutral pH and containing at least sodium caprylate to mice subsequently infected with three major Salmonella serotypes makes it possible to considerably reduce the level of splenic colonization by these bacteria. whereas this composition does not exhibit bactericidal activity at such a pH
- the pH of the pharmaceutical composition used is preferably between 6.5 and 7.5 and even more preferably between 7.1 and 7.4.
- a pH value which is particularly well suited to the use in accordance with the invention is between 7.2 and 7.3.
- radical Ri of the compounds of formula (I) represents a carbon chain substituted by a hydroxyl function
- said hydroxyl function is in position 2 when the radical Ri contains from 4 to 6 carbon atoms and in position 2 or 8 when the radical Ri contains from 7 to 9 carbon atoms.
- caprylic acid which corresponds to a compound of formula (I) in which Ri represents a saturated C 7 carbon chain
- Ri represents a saturated C 7 carbon chain
- its derivatives hydroxylated in position 2 or 8 their salts and their esters are particularly preferred.
- caprylic acid used at a neutral pH unexpectedly makes it possible to prevent Salmonella infections, while at such a pH value, this acid does not exhibit any bactericidal activity.
- the alkali metal atoms defined for the radical R are preferably chosen from sodium and potassium.
- the alkyl radicals defined for the radical R are preferably chosen from C ⁇ -C 4 alkyl radicals, among which very particularly preferred are methyl, ethyl and butyl radicals.
- sodium caprylate is used, that is to say a compound of formula (I) in which R [represents a carbon chain saturated with C and R 2 represents an atom of sodium.
- the effective amount of compound (s) of formula (I) preferably corresponds to unit doses of between 20 mM and 200 mM, and even more preferably between 50 mM and 100 mM.
- composition used in accordance with the invention may also contain one or more additional active ingredients.
- the compounds of formula (I) used in accordance with the invention can of course be formulated in an acceptable pharmaceutical vehicle consisting of one or more excipients conventionally used for the preparation of pharmaceutical compositions, such as anti-caking agents, anti- oxidants, colorants, vitamins, mineral salts, taste modifiers, smoothing agents, mounting agents, insulation agents and, in general, any excipient conventionally used in the pharmaceutical industry.
- excipients conventionally used for the preparation of pharmaceutical compositions, such as anti-caking agents, anti- oxidants, colorants, vitamins, mineral salts, taste modifiers, smoothing agents, mounting agents, insulation agents and, in general, any excipient conventionally used in the pharmaceutical industry.
- the pharmaceutical composition used according to the present invention is preferably administered orally and can be in various forms, such as in the form of tablets, capsules, oral suspensions, tablets or in any other form suitable for the mode of administration. oral.
- the pharmaceutical composition used according to the present invention can in particular be added to drinking water and / or to feeds distributed to farm animals (poultry, cattle, pigs, sheep, etc.) so as to reduce the incidence infections with Gram negative bacteria and in particular with Salmonella and limit carriage, and thus reduce the risk of subsequent contamination of humans.
- farm animals proultry, cattle, pigs, sheep, etc.
- the pharmaceutical composition used according to the present invention can also be administered to humans as a preventive medicine in order to reduce the risk of infection in people spending limited stays in a region with a high endemic, in particular of salmonellosis.
- the pharmaceutical composition used according to the present invention can also be used in humans to stop or slow down an epidemic of typhoid fever.
- the invention also comprises other provisions which will emerge from the description which follows, which refers to an example of demonstration of the activity of sodium caprylate in the prevention of salmonellosis in mice (example 1), to a comparative study of the effect of certain fatty acids on the expression of the invasion genes (example 2), as well as to the appended figures, in which:
- FIG. 1 shows the effect of the concentration of Ca 2+ ions on the expression of the iagA '-lacZ, invF'-lacZ and sipB' -lacZ fusions;
- FIG. 2 shows the effect of the concentration of sodium benzoate on the expression of the iagA '-lacZ, invF'-lacZ and sipB' -lacZ fusions
- FIG. 3 shows the effect of the concentration of sodium caprylate on the expression of the iagA '-lacZ, invF'-lacZ and sipB' -lacZ fusions
- TCS trypto-casein-soy broth
- the original standard LB medium contains 170 mM NaCl and 850 ⁇
- the favorable LB medium (high osmolarity and concentration of Ca2 + ions) was defined as being the standard LB medium modified so as to have a final concentration of 300 mM in NaCl and 5 mM in Ca2 +.
- the unfavorable LB medium (high osmolarity and low concentration of Ca2 + ions) has been defined as being the standard LB medium modified so as to have a final concentration of 300 mM in NaCl and is added with 1 mM of ethylene glycol bis- ( ⁇ -aminoethyl ether) -N, N, N ', N'-tetraacetic (EGTA) so as to create a depletion of the medium in divalent cations.
- EGTA ethylene glycol bis- ( ⁇ -aminoethyl ether) -N, N, N ', N'-tetraacetic
- a "Biotype 100” ® plate sold by the company BioMérieux is made up of 100 microcupules. Each microcupule contains a dehydrated carbon substrate, with the exception of the first well which is a control without substrate (the amount of dehydrated substrate per well is not given by the manufacturer).
- the "Biotype 100" ® plate makes it possible to study the nutritional capacity of a bacterial strain on 99 different sources of carbon (auxanogram).
- strain S. typhi Ty267 which is a derivative of the parental strain Ty2 carrying the transcriptional fusion iagA '-lacZcat (Table I), was cultivated in TCS broth for 18 hours at 37 ° C. with shaking (200 turns / min). This culture was then diluted 1/100 in favorable LB medium
- this suspension was used immediately to inoculate the 100 wells of a "Biotype 100" ® plate at the rate of 450 ⁇ l of suspension per well.
- mice By comparing the value of the ⁇ -galactosidase activity measured in a well containing a carbonaceous substrate to that of the control well without substrate, it was thus possible to determine whether a substrate had no effect on, activated or repressed the expression of the iagA '-lacZcat merger.
- I-d Experimental infection of mice
- mice The female C57B1 / 6 mice, 5-6 weeks old, used for this experiment, came from the IFF A-CREDO breeding center (L'Arbresle, France).
- mice had unlimited access to drinking water, the composition of which is given for each experiment.
- mice Seven days after infection (D + 7), the spleens of the mice thus infected were removed and homogenized separately in 1 ml of physiological water containing 0.7% NaCl.
- the number of viable bacteria per spleen was determined by plating dilutions of the homogenate on TCS agar.
- mice were infected as indicated above and the mortality of the animals was recorded for 21 days.
- aromatic acids In addition to caprylic acid, aromatic acids have been studied in order to compare their properties to those of caprylic acid.
- the aromatic acids studied were the following: benzoic acid, phenylacetic acid, 3-phenylpropionic acid and 4-phenylbutyric acid.
- aromatic acids and caprylic acid come from the company Sigma. They were all used in the form of their sodium salt and at a pH between 7.2 and 7.3.
- the aim of this preliminary step was to demonstrate that lacZ transcriptional fusions could be used for the search for environmental conditions repressing the expression of the genes present on the SPI-1 pathogenicity island.
- the S. typhi Ty267, Ty272 and Ty277 strains which carry respectively the iagA '-lacZ, invF'-lacZ and sipB'-lacZ (see Table I) fusions were cultured in favorable LB or unfavorable LB medium.
- the S. typhi strains Ty267 (iagA'-lacZ), Ty272 (invF'-lacZ) and Ty277 (sipB'-lacZ) were cultured in LB medium containing 300 mM NaCl and 5 mM CaCl (representation by a square) or 300 mM NaCl and 1 mM EGTA (representation by a diamond).
- strain S. typhi Ty267 (fusion iagA '-lacZ), suspended in favorable LB medium, was used to inoculate the "Biotype 100" ® plates.
- the ⁇ -galactosidase activity expressed by the iagA '-lacZ fusion was determined for the culture in each well. Compared to the ⁇ -galactosidase activity measured in the control cup without substrate (11250 ⁇ -galactosidase units), no substrate led to an increase in the expression of the iagA '-lacZ fusion.
- the S. typhi Ty267, Ty272 and Ty277 strains were seeded in favorable LB medium and in favorable LB medium containing different concentrations of sodium benzoate or sodium caprylate.
- the square-shaped symbols correspond to the favorable LB medium without the addition of sodium benzoate
- the diamond-shaped symbols correspond to the favorable LB medium with the addition of 5 mM of sodium benzoate
- the circle-shaped symbols correspond to the favorable LB medium with addition of
- the diamond-shaped symbols correspond to the favorable LB medium with the addition of 5 mM sodium caprylate
- the circle-shaped symbols correspond to the favorable LB medium with the addition of
- sodium benzoate or sodium caprylate very strongly represses the expression of the iagA genes, invF and sipB.
- the activity of the fusions is further reduced by 50% compared to the values measured in the favorable LB medium without sodium benzoate. If the favorable LB medium contains 1 mM sodium caprylate, the ⁇ -galactosidase activity expressed by the fusions remains low, of the order of 20% of that measured in the favorable LB medium without sodium caprylate.
- the activity of the iagA '-lacZ fusion measured after 6 hours of culture is very reduced (317 ⁇ 12 ⁇ -galactosidase units ).
- FIG. 4 The results are shown in FIG. 4, in which it can be seen that samples were taken every two hours for the measurement of the OD 6 oo (corresponding to the open symbols) and for the determination of the ⁇ -galactosidase activity (corresponding with solid symbols).
- the strains were cultivated in favorable LB medium without the addition of sodium benzoate or sodium caprylate (symbols in the form of a square in FIG. 4) and in favorable LB medium containing 5 mM of sodium benzoate (diamond shaped symbols in Figure 4) or 5 mM sodium caprylate (circle shaped symbols in Figure 4).
- sodium benzoate and sodium caprylate specifically suppress the expression of the invasion genes of the pathogenicity island SPI-1 in Salmonella.
- strain S. typhi Ty267 (fusion iagA '-lacZ) was seeded in favorable LB medium and in favorable LB medium containing the aromatic acid to be tested at the final concentration of 5 mM.
- the ⁇ -galactosidase activity of the iagA '-lacZ fusion was measured after 6 hours of incubation at 37 ° C. with shaking (200 rpm).
- Sodium 3-phenylpropionate and sodium 4-phenylbutyrate is additive because if each of them is added to the final concentration of 1 mM in the favorable LB medium, the activity of the iagA '-lacZ fusion is strongly repressed (236 ⁇ 10 ⁇ -galactosidase units), whereas this fusion is only partially repressed when the favorable LB medium is supplemented with 1 mM sodium benzoate only (5455 ⁇ 223 ⁇ -galactosidase units).
- the strain S. typhimurium C52 was used to infect C57B1 / 6 mice orally.
- C52 is equal to approximately 4.10 5 bacteria (Coynault et al, Mol. MicrobioL, 1996, 22, 149-160) and the kinetics of colonization of the spleen has been previously reported (Pardon et al, Ann. Inst. Pasteur / MicrobioL, 1986, 137B, 47-60).
- mice were orally infected with 10 8 viable bacteria (250 LD 50 ), the number of viable bacteria was then determined seven days after infection. These results show that the bacterial load in the spleen is reduced significantly significantly (p ⁇ 0.001) in mice having received drinking water having a pH between 7.2 and 7.3 and containing a mixture of 50 mM of sodium benzoate and 50 mM sodium caprylate, provided that treatment is started two days before infection.
- EDTA which like EGTA chelates divalent cations, has been studied in conjunction with the effect of sodium benzoate or sodium caprylate during murine infection with S. typhimurium.
- mice Groups of five C57B1 / 6 mice were infected orally with
- sodium caprylate no longer has a significant protective effect when its concentration is lowered to 5 or 10 mM in drinking water, whatever the infectious dose used.
- mice which had been administered drinking water of pH between 7.2 and 7.3 and containing 50 mM sodium caprylate two days before infection and for the duration of the experiment , was also infected orally with 10 7 bacteria (25 LD 5 o). One mouse died on the twelfth day of infection.
- mice used in these experiments belong to the line C57B1 / 6, which is particularly sensitive to infection by Salmonella (Mastroeni et al, Fund. Clin. ImmunoL, 1994, 2, 83- 95).
- strain S. typhi Ty267 (fusion iagA '-lacZ) was seeded in favorable LB medium and in favorable LB medium containing the fatty acid to be tested, in the form of its sodium salt, at the final concentration of 5 mM.
- the different fatty acids tested are shown in Table VI below:
- the ⁇ -galactosidase activity of the iagA '-lacZ fusion was measured after 6 hours of incubation at 37 ° C. with shaking (200 rpm).
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Abstract
Description
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Priority Applications (4)
Application Number | Priority Date | Filing Date | Title |
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EP01947582A EP1292291A2 (fr) | 2000-06-22 | 2001-06-22 | Utilisation d'acides en c 4-c10 pour la prevention des infections a bacteries a gram-negatif |
US10/312,047 US20040116523A1 (en) | 2000-06-22 | 2001-06-22 | Use of c4-c10 acids for preventing gram-negative bacterial infections |
AU2001269239A AU2001269239A1 (en) | 2000-06-22 | 2001-06-22 | Use of c4-c10 acids for preventing gram-negative bacterial infections |
CA002413284A CA2413284A1 (fr) | 2000-06-22 | 2001-06-22 | Utilisation d'acides en c4-c10 pour la prevention des infections a bacteries a gram negatif |
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FR0007992A FR2810546A1 (fr) | 2000-06-22 | 2000-06-22 | Utilisation d'acides en c2-c10 pour la prevention des infections a bacteries a gram negatif |
FR00/07992 | 2000-06-22 | ||
FR00/08383 | 2000-06-29 | ||
FR0008383A FR2810547B1 (fr) | 2000-06-22 | 2000-06-29 | Utilisation d'acides en c2-c10 pour la prevention des infections a bacteries a gram negatif |
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WO2001097791A2 true WO2001097791A2 (fr) | 2001-12-27 |
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US (1) | US20040116523A1 (fr) |
EP (1) | EP1292291A2 (fr) |
AU (1) | AU2001269239A1 (fr) |
CA (1) | CA2413284A1 (fr) |
FR (1) | FR2810547B1 (fr) |
WO (1) | WO2001097791A2 (fr) |
Cited By (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP1628622A4 (fr) * | 2003-05-20 | 2008-12-17 | Baylor Res Inst | Acides gras a cinq ou quinze carbones destines a traiter des troubles metaboliques et utilises comme complements nutritionnels |
US7611729B2 (en) | 2001-09-10 | 2009-11-03 | Lunamed Ag | Dosage forms having prolonged active ingredient release |
EP2381797B1 (fr) | 2009-01-23 | 2017-03-08 | Nutreco Nederland B.V. | Additif d'aliment de bétail et aliment de bétail comprenant des esters alcoyls d'acides gras de longueur de chaîne intermédiaire, et leur utilisation dans les aliments de bétail |
Families Citing this family (7)
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EP2237684A2 (fr) | 2008-01-08 | 2010-10-13 | Akthelia Pharmaceuticals | Agonistes pour des systèmes peptidiques antimicrobiens |
US9433209B2 (en) | 2009-03-26 | 2016-09-06 | Organic Medical Ventures, L.L.C. | Transdermal venous access locking solutions |
US9072296B2 (en) | 2009-03-26 | 2015-07-07 | Organic Medical Ventures, L.L.C. | Transdermal venous access locking solutions |
US20100249747A1 (en) * | 2009-03-26 | 2010-09-30 | Organic Medical Ventures, L.L.C. | Transdermal venous access locking solution |
US9427498B2 (en) | 2009-03-26 | 2016-08-30 | Organic Medical Ventures, L.L.C. | Syringe treated with transdermal venous access locking solutions and method of treating the syringe |
US10772343B2 (en) | 2014-11-19 | 2020-09-15 | Kansas State University Research Foundation | Chemical mitigants in animal feed and feed ingredients |
SE538436C2 (en) * | 2014-12-09 | 2016-06-28 | Perstorp Ab | Composition inhibiting gram-negative pathogens in galloanserans |
Family Cites Families (18)
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US2466663A (en) * | 1944-10-20 | 1949-04-05 | Ward Baking Co | Fungicide containing caprylic acid and its salt |
US4489097A (en) * | 1976-07-28 | 1984-12-18 | The Procter & Gamble Company | Intravenous solutions with antimicrobial agent |
EP0021504B1 (fr) * | 1979-06-25 | 1984-10-03 | THE PROCTER & GAMBLE COMPANY | Article utilisable comme cathéter ou analogue |
US4406884A (en) * | 1981-06-23 | 1983-09-27 | The Procter & Gamble Company | Topical antimicrobial composition |
GB8525061D0 (en) * | 1985-10-10 | 1985-11-13 | Bp Chem Int Ltd | Antimicrobial additives |
JPS6453627A (en) * | 1987-05-29 | 1989-03-01 | Ricoh Kk | Level shifter circuit device |
JP2581716B2 (ja) * | 1987-12-10 | 1997-02-12 | 日宝化学株式会社 | 毒素原性大腸菌症予防治療剤 |
US5434182A (en) * | 1987-12-31 | 1995-07-18 | Isaacs; Charles E. | Antibacterial fatty acid compositions |
US5234719A (en) * | 1991-06-04 | 1993-08-10 | Ecolab Inc. | Food additive sanitizing compositions |
FI100376B (fi) * | 1995-02-06 | 1997-11-28 | Kemira Oyj | Uusi säilöntäainekoostumus |
DE19505518A1 (de) * | 1995-02-10 | 1996-08-14 | Ina Dr Levi | Mittel zur Behandlung von Malaria, Hepatitis-B-Infektionen, Krebserkrankungen und systemischen opportunistischen Infektionen |
JPH08325107A (ja) * | 1995-06-01 | 1996-12-10 | Takasago Internatl Corp | 抗菌剤 |
DE69637449T2 (de) * | 1995-06-21 | 2009-03-12 | Oy Extracta Ltd. | Verwendung von alpha-hydroxysäuren zur herstellung eines arzneimittels für die behandlung von entzündungen |
JP2001509779A (ja) * | 1995-11-28 | 2001-07-24 | デー. ワイダー,マイケル | 抗菌組成物とその使用方法 |
FI103704B1 (fi) * | 1996-07-19 | 1999-08-31 | Kemira Chemicals Oy | Mikrobinvastainen koostumus, sen valmistusmenetelmä ja sen käyttö |
US5965188A (en) * | 1996-07-31 | 1999-10-12 | Anitox Corporation | Anti-bacterial amine derivatives |
JPH11266796A (ja) * | 1998-03-19 | 1999-10-05 | Zenbi Shoji Kk | 抗菌用飼料添加剤及び該抗菌用飼料添加剤を用いた抗菌方法 |
DK1294371T4 (da) * | 2000-06-20 | 2010-09-20 | Nutrition Sciences | Fedtsyrer med middellange kæder, hvilke fedtsyrer kan anvendes som antimikrobielle midler |
-
2000
- 2000-06-29 FR FR0008383A patent/FR2810547B1/fr not_active Expired - Fee Related
-
2001
- 2001-06-22 WO PCT/FR2001/001971 patent/WO2001097791A2/fr not_active Application Discontinuation
- 2001-06-22 AU AU2001269239A patent/AU2001269239A1/en not_active Abandoned
- 2001-06-22 CA CA002413284A patent/CA2413284A1/fr not_active Abandoned
- 2001-06-22 EP EP01947582A patent/EP1292291A2/fr not_active Withdrawn
- 2001-06-22 US US10/312,047 patent/US20040116523A1/en not_active Abandoned
Cited By (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US7611729B2 (en) | 2001-09-10 | 2009-11-03 | Lunamed Ag | Dosage forms having prolonged active ingredient release |
EP1628622A4 (fr) * | 2003-05-20 | 2008-12-17 | Baylor Res Inst | Acides gras a cinq ou quinze carbones destines a traiter des troubles metaboliques et utilises comme complements nutritionnels |
EP2381797B1 (fr) | 2009-01-23 | 2017-03-08 | Nutreco Nederland B.V. | Additif d'aliment de bétail et aliment de bétail comprenant des esters alcoyls d'acides gras de longueur de chaîne intermédiaire, et leur utilisation dans les aliments de bétail |
EP2381797B2 (fr) † | 2009-01-23 | 2023-05-31 | Nutreco Nederland B.V. | Additif d'aliment de bétail et aliment de bétail comprenant des esters alcoyls d'acides gras de longueur de chaîne intermédiaire, et leur utilisation dans les aliments de bétail |
Also Published As
Publication number | Publication date |
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CA2413284A1 (fr) | 2001-12-27 |
AU2001269239A1 (en) | 2002-01-02 |
FR2810547B1 (fr) | 2004-01-30 |
US20040116523A1 (en) | 2004-06-17 |
WO2001097791A3 (fr) | 2002-06-06 |
FR2810547A1 (fr) | 2001-12-28 |
EP1292291A2 (fr) | 2003-03-19 |
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