CN116585309A - Application of nitazoxanide and derivatives in preparation of polymyxin antibacterial synergists, pharmaceutical composition and sterilization method - Google Patents

Application of nitazoxanide and derivatives in preparation of polymyxin antibacterial synergists, pharmaceutical composition and sterilization method Download PDF

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CN116585309A
CN116585309A CN202310566531.6A CN202310566531A CN116585309A CN 116585309 A CN116585309 A CN 116585309A CN 202310566531 A CN202310566531 A CN 202310566531A CN 116585309 A CN116585309 A CN 116585309A
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polymyxin
nitazoxanide
antibacterial
derivatives
preparation
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张可煜
陈栋梁
郑海红
周文
王霄旸
江雪佳
王春梅
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Shanghai Veteromaru Research Institute Caas China Animal Health And Epidemiology Center Shanghan Branch Center
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    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/33Heterocyclic compounds
    • A61K31/395Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41Heterocyclic 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
    • A61K31/425Thiazoles
    • A61K31/4261,3-Thiazoles
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00Medicinal preparations containing peptides
    • A61K38/04Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
    • A61K38/12Cyclic peptides, e.g. bacitracins; Polymyxins; Gramicidins S, C; Tyrocidins A, B or C
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04Antibacterial agents
    • YGENERAL 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
    • Y02TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02ATECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
    • Y02A50/00TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
    • Y02A50/30Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

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  • Bioinformatics & Cheminformatics (AREA)
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  • Proteomics, Peptides & Aminoacids (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
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Abstract

The invention discloses application of nitazoxanide and derivatives thereof in preparation of a polymyxin antibacterial synergist, a pharmaceutical composition and a sterilization method, and belongs to the technical field of biological medicines. According to the invention, the chessboard method and the time-sterilization curve method are used for verifying that the nitazoxanide or the derivative thereof can cooperate with the sterilization activity of polymyxin to gram-negative bacteria such as escherichia coli, proteus mirabilis, klebsiella pneumoniae, salmonella and the like, and the established mouse abdominal cavity infection model is used for verifying that the combination of the nitazoxanide or the derivative thereof and the polymyxin has good treatment effect on gram-negative bacteria infection. The beneficial effects are that: nitazoxanide and its derivative are one kind of effective antibiotic synergist for colistin and may be used in combination with colistin in certain proportion to reduce the dosage of colistin medicine and treat gram negative bacteria infection.

Description

Application of nitazoxanide and derivatives in preparation of polymyxin antibacterial synergists, pharmaceutical composition and sterilization method
Technical Field
The invention belongs to the technical field of biological medicines, and particularly discloses application of nitazoxanide and derivatives thereof in preparation of a polymyxin antibacterial synergist, a pharmaceutical composition and a sterilization method.
Background
Bacterial infection is still a major problem in the medical field at present, and with the wide use of antibiotics worldwide, more and more drug-resistant bacteria are generated. Because the development cycle of new antibiotics does not catch up with the speed of bacterial resistance, the search for new methods and techniques for combating bacterial infections is currently the priority for solving the problem of antibiotic resistance. The synergistic antibacterial treatment effect produced by combining the non-antibacterial active medicaments with the antibacterial medicaments is also considered as an effective method for improving the efficacy of antibiotics, reducing the use amount of antibiotics and delaying the development of drug resistance, so that the development of safe and effective antibiotic adjuvants is a very promising effective way for treating bacterial infection.
Polymyxin was used as the last line of defense in the treatment of gram-negative "superbacteria" infections, but was also clinically presented with polymyxin-resistant bacterial strains, especially the plasmid-mediated emergence of the polymyxin resistance gene mcr-1, constitutes a great clinical threat to severe infections of the multidrug-resistant enterobacteriaceae family. It has been reported that nordihydroguaiaretic acid (chinese patent publication No. CN 113209058B), parthenolide (chinese patent publication No. CN 112957354B), fenbufen (chinese patent application publication No. CN 115414342A), artemisinin derivatives (chinese patent application publication No. CN 113082026A) and the like can increase the antibacterial effect of polymyxin by inhibiting MCR-1 resistant enzyme and other mechanisms. This provides a possible solution for finding a synergistic bactericidal effect with polymyxin, thereby reducing polymyxin usage and delaying bacterial resistance.
Nitazoxanide (Nitazoxa)nide, abbreviated as NTZ), chemical name is 2-acetoxy-N (5-nitro-2-thiazole) benzamide, its structural formula isOriginally synthesized in 1976 by the Romark laboratory in the united kingdom. At the beginning of the 21 st century, the U.S. FDA approved nitazoxanide as the first drug specifically used to treat cryptosporidium infection, marketed in multiple countries such as the united states, new zealand, australia, etc. Tizoxanide (2-hydroxy-N (5-nitro-2-thiazole) benzamide, TIZ) is a nitrozolnit derivative compound and is also a major metabolic active product. The antibacterial activity of nitazoxanide and tezoxanide is very weak, and only for anaerobic bacteria such as: the bacteria have good antibacterial effects on Bacteroides fragilis (Bacterooides fragilis), helicobacter pylori (Helicobacter pylori), campylobacter jejuni (Campylobacter jejuni), clostridium difficile (Clostridium difficile) and the like, and hardly have antibacterial activity on common microaerophilic infectious bacteria such as escherichia coli, salmonella, staphylococcus aureus and the like [ see documents In vitro evaluation of activities of nitazoxanide and tizoxanide against anaerobes and aerobic organic sms.Antimicobial agents and chemotherapy,1996,40 (10), 2266-2270, and Nitazoxanide inhibits biofilm production and hemagglutination by enteroaggregative Escherichia coli strains by blocking assembly of AafA fimbriae.Antimicobial agents and chemotherapy,2010,54 (4), 1526-1533 ].].3, 4-dichloro-N- (5-nitrothiazol-2-yl) benzamide (code WMM 2) is a nitrozolnit derivative compound having activity against gram positive bacteria such as Staphylococcus aureus, bacillus cereus, streptococcus equi, etc., but hardly having activity against gram negative bacteria [ Chinese patent application publication No. CN111777570A ]]. Up to now, no report is found about the activity of nitazoxanide and its derivatives in cooperation with polymyxin to improve gram-negative bacteria.
Disclosure of Invention
The invention aims to solve the technical problem of finding out a compound which can play a role in sterilizing with polymyxin, so as to reduce the dosage of polymyxin and delay bacterial drug resistance.
The invention solves the technical problems by the following technical means:
the first aspect of the invention provides an application of nitazoxanide and derivatives thereof in preparing a polymyxin antibacterial synergist, wherein the nitazoxanide derivatives are WMM2 (chemical name is 3, 4-dichloro-N- (5-nitrothiazol-2-yl) benzamide) and have the structural formula of
The beneficial effects are that: the invention provides a new application of nitazoxanide and its derivatives in preparing a polymyxin antibacterial synergist, and discloses that nitazoxanide and its derivatives can cooperate with polymyxin to improve the bactericidal activity of polymyxin on gram negative pathogenic bacteria, reduce the dosage of polymyxin, improve the drug effect and delay drug resistance.
Preferably, the concentration ratio of the nitazoxanide or the derivative thereof to the polymyxin is (4-128): 1.
Preferably, the concentration ratio of nitazoxanide or its derivative to polymyxin is (16-128): 1.
Preferably, the concentration ratio of the nitazoxanide or the derivative thereof to the polymyxin is (4-64): 1.
Preferably, the concentration ratio of nitazoxanide to polymyxin is 64:1.
Preferably, the concentration ratio of nitazoxanide to polymyxin is 16:1.
Preferably, the polymyxin is polymyxin B or polymyxin E.
Preferably, the antibacterial synergist is a synergist for resisting pathogenic bacteria in gram negative conditions such as escherichia coli, proteus mirabilis, klebsiella pneumoniae, salmonella and the like.
In a second aspect, the invention provides a pharmaceutical composition comprising nitazoxanide or a derivative thereof and polymyxin.
In a third aspect, the present invention provides a method for killing gram-negative bacteria, wherein the medicament used in the method is a preparation prepared from the pharmaceutical composition and pharmaceutically acceptable auxiliary materials.
The invention has the advantages that:
1. the invention provides a new application of nitazoxanide and its derivatives in preparing a polymyxin antibacterial synergist, and discloses that nitazoxanide and its derivatives can cooperate with polymyxin to improve the bactericidal activity of polymyxin on gram negative pathogenic bacteria, reduce the dosage of polymyxin, improve the drug effect and delay drug resistance.
2. The in vivo experiment shows that the combined use of the nifuratel and the polymyxin B has excellent treatment effect on the infection caused by the escherichia coli and has wide medical application in resisting gram-negative pathogenic bacteria infection.
3. According to the invention, through the study of a chessboard minimum bacteriostasis concentration test, a time-sterilization curve method, bacterial morphology, bacterial cell permeability and the like, the nitazoxanide and derivatives thereof are found to improve the sensitivity of bacteria to polymyxin, and can cooperate with the antibacterial synergism of polymyxin.
4. The bacteria used in the test of the invention mainly comprise gram negative pathogenic bacteria such as colibacillus, proteus mirabilis, klebsiella pneumoniae, salmonella and the like which are clinically separated and resistant or sensitive to polymyxin. Further, by establishing a mouse abdominal cavity infection model, the combination of nitazoxanide and polymyxin B can generate good treatment effect on gram negative pathogenic bacteria infection, and the medicine dosage of the polymyxin B is reduced.
Drawings
FIG. 1 is a time-sterilization curve of example 2 of the present invention, wherein FIG. 1A is a coliform ATCC25922 strain sensitive to polymyxin and FIG. 1B is a coliform B2 strain resistant to polymyxin;
FIG. 2 is a graph showing the results of bacterial resistance experiments in example 3 of the present invention;
FIG. 3 is an examination of bacterial ultrastructural examination of example 4 of the invention;
FIG. 4 is a graph showing the effect of example 5 of the present invention on bacterial load in mice infection model, wherein FIG. 4A shows the change in liver bacterial load and FIG. 4B shows the change in spleen bacterial load;
FIG. 5 is a graph showing the comparison of pathological changes of liver and spleen after the co-administration of example 5 of the present invention.
Detailed Description
For the purpose of making the objects, technical solutions and advantages of the embodiments of the present invention more apparent, the technical solutions in the embodiments of the present invention will be clearly and completely described in the following in conjunction with the embodiments of the present invention, and it is apparent that the described embodiments are some embodiments of the present invention, but not all embodiments. All other embodiments, which can be made by those skilled in the art based on the embodiments of the invention without making any inventive effort, are intended to be within the scope of the invention.
The raw materials or reagents used in the examples were commercially available unless otherwise specified.
The experimental methods, in which specific conditions are not noted in the following examples, are generally conducted under conventional conditions or under conditions recommended by the manufacturer.
Example 1:
minimum inhibitory concentration test
Respectively adding polymyxin working solution and nitazoxanide (or WMM 2) working solution with different concentrations into sterilized 96-well culture medium, performing multiple dilution according to chessboard method, and adding final concentration of 5×10 5 The CFU/mL bacterial suspension is placed in a 37 ℃ incubator for culturing for 16-20 hours, MIC values of polymyxin and nitazoxanide which are used singly and in combination are determined, and partial bacteriostasis concentration index (FIC) is calculated.
When the antibiotic (A) and the non-antibacterial drug (B) are used independently, the minimum antibacterial concentration is MICA and MICB respectively, and after the combination is used, a new MICa and MICb can appear, and the FIC value calculation formula is as follows:
when the FIC is less than 0.5, the two medicines can be judged to be synergistic, when the FIC is less than or equal to 0.5 and less than or equal to 2, the medicines are added, and when the FIC is more than or equal to 2, the medicines are antagonistic. The results are shown in Table 1:
TABLE 1 MIC and FIC values of Nitroxazonites in combination with polymyxin B for E.coli and Salmonella
As can be seen from Table 1, nitazoxanide has no bacteriostatic effect, and the combination with polymyxin B can reduce the MIC value of polymyxin to coliform bacteria and salmonella by 8 times, and the FIC values of the polymyxin B indicate that both the nitazoxanide and the polymyxin have a synergistic effect.
Considering that both nitazoxanide and WMM2 do not have gram negative bacteria inhibiting effect, MIC values are greater than 200 μg/mL, the minimum inhibitory concentration MICB is not accurate in calculating FIC, and the drug synergy of nitazoxanide (or WMM 2) and polymyxin is further evaluated using the zero interaction potency (Zip) scoring method of synergy Finder. The specific method is that when the MIC is detected by the chessboard method, the OD value of each hole is measured by an enzyme-labeled instrument, and the bacterial growth condition of each hole reflected by the OD value is brought into the synergy Finder software to calculate the Zip score. When Zip >0, the two medicaments can be judged to be synergistic; when zip=0, there is no interaction; antagonism occurs when Zip <0. The results are shown in Table 2:
TABLE 2 Zip score for Nitroxazonit or WMM2 in combination with polymyxin
Note that: -indicating that no detection is performed.
As can be seen from Table 2, nitazoxanide and its derivative WMM2 can synergistically kill E.coli, klebsiella pneumoniae and Proteus mirabilis.
Example 2:
time-sterilization Curve test
Single bacterial colonies from the plates were inoculated into LB medium overnight for cultivation to reach about 10 8 Concentration of CFU/ml. Next, bacteria in the logarithmic growth phase were added to the antibiotic-free control group, polymyxin B group, nitazoxanide group, polymyxin B and nitazoxanide combination group at a final bacterial concentration of 1X 10 5 CFUs/ml after incubation 10 μl of bacterial suspension was removed from each group for colony counting at 0h, 0.5h, 2h, 4h, 8h, 12h, 24h, respectively. The time-sterilization curve is plotted and the result is shown in figure 1.
Conclusion: nitroxanim in combination with polymyxin B was able to kill both polymyxin-sensitive E.coli ATCC25922 strain (FIG. 1A) and polymyxin-resistant E.coli B2 strain (FIG. 1B) thoroughly within 2h and 4h, respectively.
FIG. 1 is a time-sterilization curve of example 2 of the present invention, wherein FIG. 1A is a coliform ATCC25922 strain sensitive to polymyxin and FIG. 1B is a coliform B2 strain resistant to polymyxin.
Example 3:
bacterial drug resistance experiment
Colibacillus ATCC25922 strain was treated cooperatively with 0.5. Mu.g/mL of polymyxin B, 64. Mu.g/mL of nitazoxanide and the mixture of both drugs, and drug incubation and passage were performed to determine MIC and FIC of 5, 10, 15, 20, 25, 30-generation bacteria, and bacteria without any drug passage were used as a control, and whether or not a change was occurred to examine acquired drug resistance, and the results are shown in FIG. 2.
Conclusion: after serial passage, the bacterial group incubated with polymyxin alone and with both drugs has developed higher resistance to polymyxin. However, the synergistic FIC results were tested by the checkerboard method and found that the combination of polymyxin B and nitazoxanide still had a good synergistic effect after drug passage-induced resistance (FIC <0.5, fig. 2). Therefore, the combined drug has a synergistic effect after drug resistance induction.
Example 4:
bacterial ultrastructural inspection
Bacteria were treated with 0.5 μg/mL polymyxin, 32 μg/mL nitazoxanide and the combination of the two drugs, respectively, with a blank control. After 2h of drug treatment, centrifuging at 4000rpm for 10min, washing the drug and the culture medium with PBS, adding glutaraldehyde with a final concentration of 2.5%, standing at normal temperature for 6h, and standing in a refrigerator at 4 ℃ overnight for fixation. And (5) after the sample is subjected to slice staining according to the requirement, observing the sample under a transmission electron microscope.
Conclusion: the colistin group has a small number of bacteria destroyed, the individual bacteria have a content leakage, a small part of bacterial cell membranes are broken, and most of bacteria are still in a normal state. Compared with the control group, the nitazoxanide group has the phenomenon of chromatin site coagulation, complete cell wall morphology of the cell membrane, clear cell membrane and cell wall structure morphology and no cell rupture condition. In the synergistic group with the same concentration, the destroyed proportion of the bacteria is obviously increased, the cell membrane and the cell wall of the bacteria are obviously damaged, most bacterial chromatin is coagulated, cytoplasmic leakage condition appears outside the bacteria, villiated bulges are arranged on the surface of the bacteria, the whole bacterial destruction condition is serious, and the staining condition is shallower than that of normal bacteria (shown in figure 3).
Example 5:
colony colonization test for whole body infection of mice
We select representative colibacillus to build the model of mouse whole body infection
After ICR mice (male, about 20 g) were fixed, a suspension of E.coli (ATCC 25922) was intraperitoneally injected (1.5X10) 8 CFUs), a model of systemic infection in mice was established. Immediately after the intraperitoneal inoculation of the mice with bacteria, 1.5mg/kg.bw of polymyxin B and 24mg/kg.bw of nitazoxanide, polymyxin E (1.5 mg/kg.bw) were combined with nitazoxanide (24 mg/kg.bw), and the mice were administered 6 hours after infection. The positive control group was given 200 μl of DMSO blank solvent without any drug for treatment; a solvent control group of uninfected mice was additionally established, and 200 μl of DMSO blank solvent was subcutaneously administered to investigate the safety of the DMSO solvent used. After administration according to the administration scheme, mice are sacrificed 24 hours after administration, the livers of the mice are weighed, homogenized, plated for counting after dilution by a multiple ratio, and the liver and spleen tissues are subjected to HE staining to observe pathological changes. The results are shown in FIGS. 4 and 5.
Conclusion: after the combined treatment of the nifuratel and the polymyxin B, the colony colonization number of liver tissues (figure 4A) and spleen tissues (figure 4B) of the mice is obviously reduced, the effect of the combined treatment group is stronger than that of a polymyxin B single treatment group, and the effect of the polymyxin B single treatment group is also obvious compared with that of the nifuratel single treatment group or a blank group. HE staining results (fig. 5) showed that the combined administration significantly reduced the inflammatory response induced by e.coli infection.
Example 6:
this embodiment differs from embodiment 3 in that: the procedure of example 3 was repeated except that "64. Mu.g/mL of nitazoxanide" was changed to "2. Mu.g/mL of nitazoxanide".
The synergistic effect produced by the combination of polymyxin B and nitazoxanide of this example is slightly lower than that of example 3.
The above embodiments are only for illustrating the technical solution of the present invention, and are not limiting; although the invention has been described in detail with reference to the foregoing embodiments, it will be understood by those of ordinary skill in the art that: the technical scheme described in the foregoing embodiments can be modified or some technical features thereof can be replaced by equivalents; such modifications and substitutions do not depart from the spirit and scope of the technical solutions of the embodiments of the present invention.

Claims (10)

1. The application of nitazoxanide and its derivative in preparing colistin antibiotic synergist is characterized in that the nitazoxanide derivative is WMM2 (chemical name is 3, 4-dichloro-N- (5-nitrothiazole-2-yl) benzamide) with the structural formula of
2. The use of nitazoxanide and its derivatives according to claim 1 for the preparation of a polymyxin antibacterial potentiator, characterized in that the concentration ratio of nitazoxanide or its derivatives to polymyxin is (4-128): 1.
3. The use of nitazoxanide and its derivatives according to claim 2 for the preparation of a polymyxin antibacterial potentiator, characterized in that the concentration ratio of nitazoxanide or its derivatives to polymyxin is (4-64): 1.
4. The use of nitazoxanide and its derivatives according to claim 2 for the preparation of a polymyxin antibacterial potentiator, characterized in that the concentration ratio of nitazoxanide or its derivatives to polymyxin is (16-128): 1.
5. The use of nitazoxanide and its derivatives according to claim 2 for the preparation of a polymyxin antibacterial potentiator, characterized in that the concentration ratio of nitazoxanide to polymyxin is 16:1.
6. The use of nitazoxanide and its derivatives according to claim 2 for the preparation of a polymyxin antibacterial potentiator, characterized in that the concentration ratio of nitazoxanide to polymyxin is 64:1.
7. The use of nitazoxanide and its derivatives according to claim 1 for the preparation of a polymyxin antibiotic potentiator, characterized in that the polymyxin is polymyxin B or polymyxin E.
8. The use of nitazoxanide and its derivatives in the preparation of a polymyxin antibacterial potentiator according to claim 1, characterized in that said antibacterial potentiator is a potentiator against gram negative pathogenic bacteria such as escherichia coli, proteus mirabilis, klebsiella pneumoniae and salmonella.
9. A pharmaceutical composition comprising nitazoxanide or a derivative thereof according to claim 1 and polymyxin.
10. A method of killing gram negative bacteria, wherein the medicament used in the method is a preparation prepared from the pharmaceutical composition of claim 9 and pharmaceutically acceptable excipients.
CN202310566531.6A 2023-05-18 2023-05-18 Application of nitazoxanide and derivatives in preparation of polymyxin antibacterial synergists, pharmaceutical composition and sterilization method Pending CN116585309A (en)

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN117064881A (en) * 2023-09-27 2023-11-17 南京农业大学 Application of nitazoxanide in preparing potentiator for resisting MCR-1 and NDM-5 positive strains

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN117064881A (en) * 2023-09-27 2023-11-17 南京农业大学 Application of nitazoxanide in preparing potentiator for resisting MCR-1 and NDM-5 positive strains
CN117064881B (en) * 2023-09-27 2024-03-15 南京农业大学 Application of nitazoxanide in preparing potentiator for resisting MCR-1 and NDM-5 positive strains

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