CN115487182B - Application of isothiazolinone as synergist of antibacterial drug - Google Patents

Application of isothiazolinone as synergist of antibacterial drug Download PDF

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CN115487182B
CN115487182B CN202211346103.4A CN202211346103A CN115487182B CN 115487182 B CN115487182 B CN 115487182B CN 202211346103 A CN202211346103 A CN 202211346103A CN 115487182 B CN115487182 B CN 115487182B
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antibacterial
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mug
isothiazolinone
benzisothiazolinone
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CN115487182A (en
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季辉
万荣峰
彭麟
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Nanjing Aili Veterinary Research Institute Co ltd
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    • A61K31/00—Medicinal preparations containing organic active ingredients
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    • 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
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    • 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
    • A61K31/7036—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin having at least one amino group directly attached to the carbocyclic ring, e.g. streptomycin, gentamycin, amikacin, validamycin, fortimicins
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    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents
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    • Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
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Abstract

The invention discloses application of isothiazolinone as a synergist of an antibacterial drug, and belongs to the technical field of medicines. Experimental study shows that when isothiazolinone is combined with aminoglycosides, polypeptides, fluoroquinolones and other antibacterial drugs, the dosage of the antibacterial drugs can be reduced, the antibacterial effect on bacteria can be ensured under the condition of reducing the dosage of the antibacterial drugs, and the antibacterial agents have obvious synergistic effect on clinically separated drug-resistant strains.

Description

Application of isothiazolinone as synergist of antibacterial drug
Technical Field
The invention belongs to the technical field of medicines, and particularly relates to application of isothiazolinone as a synergist of an antibacterial drug.
Background
Isothiazolinone is a novel efficient broad-spectrum bactericide, has the advantages of high efficiency, low toxicity, environmental friendliness and the like, has gradually replaced a plurality of toxic low-efficiency bactericides such as mercury and the like since being developed into the field of bactericidal biocides, and is widely applied to the fields such as agriculture, industry and the like (Li Shichang and the like, synthetic material aging and application, 47 (7), 120-123 (2018)). It is widely used in various fields of industrial production for mold resistance and corrosion resistance, and is also used as a main antibacterial preservative in some personal care products (cosmetics for daily use, washing products, etc.). The sterilization mechanism of isothiazolinones is mainly an electrophilic activity bactericide, and the active part on the isothiazolinones heterocycle forms hydrogen bonds with bases on DNA molecules in proteins in bacteria and is adsorbed on cells of bacteria to attack cell nucleophilicity, so that the structure of the DNA in the cells is destroyed, and related physiological and biochemical reactions and metabolic activities are lost, so that the cells die (Qu Zhen, pharmaceutical chemicals, 42 (9), 103 (2016)).
Substances having inhibitory and/or bactericidal actions on bacteria and other microorganisms are collectively referred to as antibacterial agents, which mainly include synthetic antibacterial agents (quinolones and the like) and antibiotics. Antibiotics are metabolites of microorganisms (bacteria, fungi, and actinomycetes) that kill or inhibit other pathogenic microorganisms at appropriate concentrations. Antibacterial drugs play an important role in the prevention and control of diseases in humans and animals. However, microorganisms exposed to the antimicrobial agent may also act against the antimicrobial agent by altering metabolic pathways or producing corresponding inactivating substances, thereby reducing the pharmacodynamic effects of the antimicrobial agent or even creating resistance. At present, similar medicines such as potassium clavulanate, sulbactam and the like which can improve the drug effect of antibacterial medicines and reduce the drug dosage can compete with beta-lactamase inhibitors, and the medicines are combined with beta-lactam antibacterial medicines, so that obvious synergistic effect can generally appear and the antibacterial activity can be greatly improved; trimethoprim (TMP) is a bacterial dihydrofolate reductase inhibitor, which belongs to a sulfonamide antibacterial drug synergist. Therefore, the development of the antibacterial synergist has important significance for improving the application of antibacterial medicines.
Disclosure of Invention
The invention aims to provide application of isothiazolinone as a synergist of an antibacterial drug.
In order to achieve the above object, the present invention adopts the following technical scheme:
the isothiazolinone is used as the synergist of antibiotic medicine.
Further, the isothiazolinone is selected from methyl isothiazolinone, methyl chloroisothiazolinone or benzisothiazolinone.
Further, the antibacterial agent is an antibacterial agent against gram-negative bacteria.
Further, the antibacterial agent against gram-negative bacteria is selected from aminoglycoside antibacterial agents, polypeptide antibacterial agents or fluoroquinolone antibacterial agents.
Further preferably, the antibacterial agent against gram negative bacteria is selected from colistin sulfate, enrofloxacin, neomycin sulfate, gentamicin sulfate or difloxacin.
An antimicrobial pharmaceutical composition comprising: isothiazolinones, antibacterial agents, and pharmaceutically acceptable carriers and/or excipients;
the weight ratio of the isothiazolinone to the antibacterial drug is 1:2-4:1.
Further, the isothiazolinone is selected from methyl isothiazolinone, methyl chloroisothiazolinone or benzisothiazolinone.
Further, the antibacterial agent is an antibacterial agent against gram-negative bacteria.
Further, the antibacterial agent against gram-negative bacteria is selected from aminoglycoside antibacterial agents, polypeptide antibacterial agents or fluoroquinolone antibacterial agents.
Further preferably, the antibacterial agent against gram negative bacteria is selected from colistin sulfate, enrofloxacin, neomycin sulfate, gentamicin sulfate or difloxacin.
Experimental study shows that when the isothiazolinone is combined with the antibacterial drug, the dosage of the antibacterial drug can be reduced, the antibacterial effect of the isothiazolinone on bacteria can be ensured under the condition of reducing the dosage of the antibacterial drug, and the isothiazolinone has obvious synergism on clinically separated drug-resistant strains. Thus, isothiazolinones can be used as potentiators of antibacterial agents.
The invention provides a new application of isothiazolinone as an antibacterial drug synergist, and also provides a new solution for prevention and control of drug-resistant bacteria. On the one hand, isothiazolinone is used as an antibacterial drug synergist, and the effective dosage of the antibacterial drugs such as aminoglycosides, polypeptides, fluoroquinolones and the like can be reduced, so that the toxic and side effects of the drugs are reduced to a certain extent, and the drug cost is reduced. On the other hand, the isothiazolinone can restore the function of the antibacterial drug on drug-resistant bacteria, effectively treat bacterial infection, especially drug-resistant bacteria infection, and has important clinical application value.
Detailed Description
The inventor has studied deeply for a long time, and has found that isothiazolinone compounds have good synergistic effect on a series of antibacterial drugs, especially aminoglycoside antibacterial drugs, polypeptide antibacterial drugs and fluoroquinolone antibacterial drugs. On this basis, the inventors completed the present invention.
The following describes the invention in more detail. The description of these embodiments is provided to assist understanding of the present invention, but is not intended to limit the present invention. In addition, the technical features of the embodiments of the present invention described below may be combined with each other as long as they do not collide with each other.
Example 1
In vitro combined sensitization assay (FIC assay) of escherichia coli and salmonella by combined action of Methylisothiazolinone (MIT) and Colistin sulfate (Colistin).
1 reagent
Methylisothiazolinone and colistin sulfate.
Strain 2
Chicken escherichia coli SD-02 was clinically isolated, and salmonella pullorum AH-05 was clinically isolated.
3 Medium
Nutrient broth medium and nutrient agar medium.
4 instrument
Constant temperature incubator, constant temperature shaking table, micropipette.
5 test method
5.1 Minimum Inhibitory Concentration (MIC) determination
(1) The drug stock solution was diluted 10-fold with the broth to obtain a drug solution for use at a concentration of 256. Mu.g/mL. Then carrying out continuous double-ratio dilution, taking 100 mu L of each diluted liquid medicine, and sequentially adding the diluted liquid medicine into 1 st to 11 th holes of the micro-pore plate according to the concentration from high to low, wherein the corresponding concentration of each hole is 256 mu g/mL, 128 mu g/mL, 64 mu g/mL, 32 mu g/mL, 16 mu g/mL, 8 mu g/mL, 4 mu g/mL, 2 mu g/mL, 1 mu g/mL, 0.5 mu g/mL and 0.25 mu g/mL. In addition, 100 μl of MH broth without drug was added to the blank wells (well 12) adjacent to the lowest concentration wells as a negative control.
(2) 100. Mu.L of the prepared turbidity was taken up to 10, respectively 6 The CFU/mL test bacterial liquid is added into the 1 st to 11 th holes of the micro-porous plate, and the final concentration of the liquid medicine corresponding to each hole is respectively changed into 128 mug/mL, 64 mug/mL and 32 mug from high to lowg/mL, 16. Mu.g/mL, 8. Mu.g/mL, 4. Mu.g/mL, 2. Mu.g/mL, 1. Mu.g/mL, 0.5. Mu.g/mL, 0.25. Mu.g/mL, 0.125. Mu.g/mL; at the same time, 100. Mu.L of the bacteria-free broth was again added to the negative control well (well 12).
(3) Mixing the fungus liquid and the liquid medicine, covering the micro-pore plate, fixing with adhesive tape, placing into enamel square tray filled with wet gauze, and standing in a constant temperature incubator at 37deg.C for culturing for 24 hr.
(4) After 24h of culture, taking out the micro-pore plate, observing under the light lined with a black bottom plate, wherein the culture solution in the micro-pore plate is in diffuse turbidity or the U-shaped bottom is in circular or silk screen precipitation during bacterial growth, and the lowest drug concentration without bacterial growth holes is the MIC of the drug.
5.2 determination of Combined drug sensitivity (FIC)
The combination was performed at concentrations of 8-fold, 4-fold, 2-fold, 1/2-fold, etc. of each of the MIC values using a broth dilution checkerboard method.
50 mu L of diluted solution of methyl isothiazolinone with different concentrations is added from the 1 st to 5 th transverse rows on a micro-pore plate, and the 6 th transverse rows are used as independent drug sensitive control of colistin sulfate (100 mu L) without methyl isothiazolinone; 50 mu L of colistin sulfate diluted solutions with different concentrations are added from column 1 to column 5 according to the column 6, and the column 6 is used as a single drug sensitive control of methylisothiazolinone (100 mu L) without colistin sulfate; then 100. Mu.L of broth was added to each single drug control, so that the amount of broth in each well was 200. Mu.L. Culturing at proper temperature for 16-24 hr. And (3) observing the growth condition of bacteria with naked eyes, recording MIC values of the combined application, and calculating the FIC index during the combined application of the medicines.
6 result determination
FIC index = MIC of a combination of a first drug/MIC of a first drug alone + MIC of a combination of a second drug/MIC of a second drug alone
FIC index Action
FIC index is less than or equal to 0.5 Synergistic effect
0.5<FIC index of 1 or less Additive effect
1<FIC index of 2 or less Irrelevant effect
FIC index>2 Antagonism of
Results 7 results
The FIC for E.coli was 0.5 for methylisothiazolinone in combination with colistin sulfate.
The FIC for salmonella for methylisothiazolinone in combination with colistin sulfate was 0.375.
From the above test results, it can be seen that methylisothiazolinone has a synergistic effect on the antibacterial effect of colistin sulfate, and exhibits synergism.
Example 2
Combination of Benzisothiazolinone (BIT) and Enrofloxacin (EN) in vitro combined sensitization test (FIC assay) against E.coli and Salmonella.
1 reagent
Benzisothiazolinone and enrofloxacin.
Strain 2
Chicken escherichia coli SD-02 was clinically isolated, and salmonella pullorum AH-05 was clinically isolated.
3 Medium
Nutrient broth medium and nutrient agar medium.
4 instrument
Constant temperature incubator, constant temperature shaking table, micropipette.
5 test method
As in example 1.
6 result determination
As in example 1.
Results 7 results
The FIC for E.coli was 0.5 for benzisothiazolinone in combination with enrofloxacin.
The FIC for Salmonella in combination of benzisothiazolinone and enrofloxacin is 0.5.
From the above test results, it can be seen that benzisothiazolinone has a synergistic effect on the antibacterial effect of enrofloxacin, exhibiting synergism.
Example 3
Combination of methyl Chloroisothiazolinone (CMIT) with neomycin sulphate (NEO) in vitro combined sensitization assay (FIC assay) for escherichia coli and salmonella.
1 reagent
Methyl chloroisothiazolinone, neomycin sulfate.
Strain 2
Chicken escherichia coli SD-02 was clinically isolated, and salmonella pullorum AH-05 was clinically isolated.
3 Medium
Nutrient broth medium and nutrient agar medium.
4 instrument
Constant temperature incubator, constant temperature shaking table, micropipette.
5 test method
As in example 1.
6 result determination
As in example 1.
Results 7 results
The FIC for E.coli was 0.5 for methyl chloroisothiazolinone in combination with neomycin sulfate.
The FIC for salmonella was 0.5 for methyl chloroisothiazolinone in combination with neomycin sulfate.
From the above test results, it can be seen that methyl chloroisothiazolinone has a synergistic effect on the antibacterial effect of neomycin sulfate, and exhibits synergy.
Example 4
MIC determination of clinically isolated escherichia coli by combined action of Methylisothiazolinone (MIT), methylchloroisothiazolinone (CMIT), benzisothiazolinone (BIT) and Colistin sulfate.
1 reagent
Methyl isothiazolinone, methyl chloroisothiazolinone, benzisothiazolinone and colistin sulfate.
Strain 2
Chicken colibacillus SD-04, SD-05, JS-11, JS-13 and AH-02 are clinically isolated.
3 Medium
Nutrient broth medium and nutrient agar medium.
4 instrument
Constant temperature incubator, constant temperature shaking table, micropipette.
5 test method
(1) The drug stock solution was diluted 10-fold with the broth to obtain a drug solution for use at a concentration of 256. Mu.g/mL. Then carrying out continuous double-ratio dilution, taking 100uL of each diluted liquid medicine, and sequentially adding the 100uL of diluted liquid medicine into 1 st to 11 th holes of the micro-pore plate according to the concentration from high to low, wherein the corresponding concentration of each hole is 256 mug/mL, 128 mug/mL, 64 mug/mL, 32 mug/mL, 16 mug/mL, 8 mug/mL, 4 mug/mL, 2 mug/mL, 1 mug/mL, 0.5 mug/mL and 0.25 mug/mL. In addition, 100. Mu.L of the drug-free broth was added to the blank wells (well 12) adjacent to the lowest concentration well as a negative control.
(2) 100. Mu.L of the prepared turbidity was taken up to 10, respectively 6 Adding the CFU/mL test bacterial liquid into the 1 st to 11 th holes of the micro-porous plate, and adding the test bacterial liquid into each hole pairThe final concentration of the liquid medicine is changed from high to low to 128 mug/mL, 64 mug/mL, 32 mug/mL, 16 mug/mL, 8 mug/mL, 4 mug/mL, 2 mug/mL, 1 mug/mL, 0.5 mug/mL, 0.25 mug/mL and 0.125 mug/mL respectively; at the same time, 100. Mu.L of the bacteria-free broth was again added to the negative control well (well 12).
(3) Mixing the fungus liquid and the liquid medicine, covering the micro-pore plate, fixing with adhesive tape, placing into enamel square tray filled with wet gauze, and standing in a constant temperature incubator at 37deg.C for culturing for 24 hr.
(4) After 24h of culture, taking out the micro-pore plate, observing under the light lined with a black bottom plate, wherein the culture solution in the micro-pore plate is in diffuse turbidity or the U-shaped bottom is in circular or silk screen precipitation during bacterial growth, and the lowest drug concentration without bacterial growth holes is the MIC of the drug.
(5) After the MIC of methyl isothiazolinone, methyl chloroisothiazolinone and benzisothiazolinone are measured, the chemical liquid with 1/4 times of MIC concentration is respectively matched with colibacillus sulfate solutions with different concentrations to measure the MIC of the colibacillus.
6 results
The test results show that the addition of isothiazolinone reduces the Minimum Inhibitory Concentration (MIC) of coliform in clinically isolated chickens, and shows that the coliform has synergistic effect on the antibacterial effect of coliform sulfate.
Example 5
MIC determination of clinically isolated salmonella by combined action of benzisothiazolinone and gentamicin sulfate, colistin sulfate and difluorofloxacin
1 reagent
Benzisothiazolinone (BIT), gentamicin sulfate (GM), colistin sulfate, and Difloxacin (DF).
Strain 2
Salmonella gallinarum HN-011, HN-102, JS-22, AH-03 and AH-34 are clinically isolated.
3 Medium
Nutrient broth medium and nutrient agar medium.
4 instrument
Constant temperature incubator, constant temperature shaking table, micropipette.
5 test method
(1) The drug stock solution was diluted 10-fold with the broth to obtain a drug solution for use at a concentration of 256. Mu.g/mL. Then carrying out continuous double-ratio dilution, taking 100uL of each diluted liquid medicine, and sequentially adding the 100uL of diluted liquid medicine into 1 st to 11 th holes of the micro-pore plate according to the concentration from high to low, wherein the corresponding concentration of each hole is 256 mug/mL, 128 mug/mL, 64 mug/mL, 32 mug/mL, 16 mug/mL, 8 mug/mL, 4 mug/mL, 2 mug/mL, 1 mug/mL, 0.5 mug/mL and 0.25 mug/mL. In addition, 100. Mu.L of the drug-free broth was added to the blank wells (well 12) adjacent to the lowest concentration well as a negative control.
(2) 100. Mu.L of the prepared turbidity was taken up to 10, respectively 6 The CFU/mL test bacterial liquid is added into the 1 st to 11 th holes of the micro-porous plate, and the final concentration of the corresponding liquid medicine of each hole is changed into 128 mug/mL, 64 mug/mL, 32 mug/mL, 16 mug/mL, 8 mug/mL, 4 mug/mL, 2 mug/mL, 1 mug/mL, 0.5 mug/mL, 0.25 mug/mL and 0.125 mug/mL from high to low; at the same time, 100. Mu.L of the bacteria-free broth was again added to the negative control well (well 12).
(3) Mixing the fungus liquid and the liquid medicine, covering the micro-pore plate, fixing with adhesive tape, placing into enamel square tray filled with wet gauze, and standing in a constant temperature incubator at 37deg.C for culturing for 24 hr.
(4) After 24h of culture, taking out the micro-pore plate, observing under the light lined with a black bottom plate, wherein the culture solution in the micro-pore plate is in diffuse turbidity or the U-shaped bottom is in circular or silk screen precipitation during bacterial growth, and the lowest drug concentration without bacterial growth holes is the MIC of the drug.
(5) After the MIC of the benzisothiazolinone is measured, the MIC of salmonella is measured by matching a 1/4 times MIC concentration liquid medicine with gentamycin sulfate, colistin sulfate and difluoro-air-acid solution with different concentrations. The measurement process and method are the same as those of (1-4).
6 results
The test results show that the addition of isothiazolinone reduces the Minimum Inhibitory Concentration (MIC) of gentamicin sulfate, colistin sulfate and difloxacin on clinically separated salmonella gallinarum, and has synergistic effect on the antibacterial effect of gentamicin sulfate, colistin sulfate and difloxacin.
Comparative example 1
Benzisothiazolinone (BIT) in combination with Amoxicillin (AMO) for in vitro combined sensitization assay (FIC assay) of E.coli and Salmonella.
1 reagent
Benzisothiazolinone and amoxicillin.
Strain 2
Chicken escherichia coli SD-02 was clinically isolated, and salmonella pullorum AH-05 was clinically isolated.
3 Medium
Nutrient broth medium and nutrient agar medium.
4 instrument
Constant temperature incubator, constant temperature shaking table, micropipette.
5 test method
As in example 1.
6 result determination
As in example 1.
Results 7 results
The FIC for E.coli was 1.5 for benzisothiazolinone in combination with amoxicillin.
The FIC for Salmonella in combination with benzisothiazolinone and amoxicillin was 1.
From the above test results, it can be seen that the antibacterial effect of benzisothiazolinone on amoxicillin is judged to be additive or irrelevant from FIC, and no synergistic effect is obtained.
Comparative example 2
The combined action of Methylisothiazolinone (MIT) with Tilmicosin (TIM) was used for in vitro combined drug susceptibility testing (FIC assay) of E.coli and Salmonella.
1 reagent
Methyl isothiazolinone and tilmicosin.
Strain 2
Chicken escherichia coli SD-02 was clinically isolated, and salmonella pullorum AH-05 was clinically isolated.
3 Medium
Nutrient broth medium and nutrient agar medium.
4 instrument
Constant temperature incubator, constant temperature shaking table, micropipette.
5 test method
As in example 1.
6 result determination
As in example 1.
Results 7 results
The FIC for E.coli was 1.5 for benzisothiazolinone in combination with amoxicillin.
The FIC for Salmonella was 1.5 for benzisothiazolinone in combination with amoxicillin.
From the above test results, it can be seen that the antibacterial effect of benzisothiazolinone on tilmicosin was judged to be additive or irrelevant from FIC, and no synergistic effect was obtained.
In conclusion, the isothiazolinone and the antibacterial drugs such as aminoglycosides, polypeptides, fluoroquinolones and the like can produce synergistic effect, so the isothiazolinone and the antibacterial drugs can be used as the synergistic agent of the drugs.
The embodiments of the present invention have been described in detail above, but the present invention is not limited to the described embodiments. It will be apparent to those skilled in the art that various changes, modifications, substitutions and alterations can be made to these embodiments without departing from the principles and spirit of the invention, and yet fall within the scope of the invention.

Claims (2)

1. The application of benzisothiazolinone in preparing synergist of antibacterial drug is characterized in that the bacteria are salmonella, and the antibacterial drug is selected from colistin sulfate, gentamicin sulfate or difloxacin.
2. An antibacterial pharmaceutical composition, which is characterized by comprising benzisothiazolinone, an antibacterial agent and a pharmaceutically acceptable carrier;
the weight ratio of the benzisothiazolinone to the antibacterial drug is 1:2-4:1;
the antibacterial drug is selected from colistin sulfate, gentamicin sulfate or difluoro-floxacin;
the bacteria are salmonella.
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