CN119326870A - Application of magnolol combined with polymyxin in the preparation of drugs for anti-Salmonella infection - Google Patents
Application of magnolol combined with polymyxin in the preparation of drugs for anti-Salmonella infection Download PDFInfo
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- CN119326870A CN119326870A CN202411515472.0A CN202411515472A CN119326870A CN 119326870 A CN119326870 A CN 119326870A CN 202411515472 A CN202411515472 A CN 202411515472A CN 119326870 A CN119326870 A CN 119326870A
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- 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
- A61K31/045—Hydroxy compounds, e.g. alcohols; Salts thereof, e.g. alcoholates
- A61K31/05—Phenols
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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- A61K38/00—Medicinal preparations containing peptides
- A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
- A61K38/12—Cyclic peptides, e.g. bacitracins; Polymyxins; Gramicidins S, C; Tyrocidins A, B or C
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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Abstract
The application belongs to the technical field of biological medicines, and discloses application of magnolol as a polymyxin synergist in inhibition of salmonella. The application discovers that the magnolol and polymyxin have good synergistic effect on the experiment of salmonella in vitro and in vivo. Compared with the traditional method for killing salmonella by combining antibiotics and antibiotics, the synergistic sterilization of the plant-derived magnolol and polymyxin is not easy to induce the generation of bacterial drug resistance, and the magnolol has the characteristics of wide sources, low price and good treatment effect, and has good research and application significance for the synergistic substitution of the antibiotics and the solution of bacterial drug resistance.
Description
Technical Field
The invention belongs to the technical field of biological medicines, and discloses application of magnolol as a polymyxin synergist in inhibition of salmonella.
Background
Salmonella is a gram-negative bacterium, and after people or cultured animals eat food contaminated by salmonella, it can cause food-borne diseases, which can cause diseases ranging from local gastroenteritis to systemic diseases. The problem of drug resistance of salmonella has been a threat to global public health, and as salmonella drug resistance rate increases in clinical testing, and the supply of novel antibiotics is limited, polymyxin has been used as the last line of defense for antibiotics to treat multidrug-resistant salmonella.
From the 50 s of the last century, polymyxins have been used as antibiotics against clinical infections caused by gram-negative bacteria in human and veterinary settings. However, polymyxin use is susceptible to clinical toxicity, which has led to a significant reduction in its use in the last 80 th century. However, as the harm of the drug-resistant bacteria increases, the polymyxin is reused as a final treatment means for treating the multiple drug-resistant bacteria. Since 2016, plasmid-mediated mobile polymyxin resistance gene (mcr-1) was reported, polymyxin resistance was a new public health threat worldwide. Polymyxins have been inactive in the veterinary field of China and effectively reduce the detection rate of coliform bacteria resistant to polymyxins. However, in clinical treatment, polymyxin is also a very important antibiotic drug.
The natural compound with synergistic effect with polymyxin is extracted from the natural compound library, so that the sensitivity of polymyxin-resistant enterobacteriaceae bacteria to polymyxin can be effectively recovered, the method is one of effective methods for excavating antibiotics and strategies for solving the problem of bacterial resistance, the problem of polymyxin resistance based on enterobacteriaceae bacteria is quite important and prominent, and therefore, the screening of effective polymyxin synergist for treating enterobacteriaceae infection of drug-resistant polymyxin is urgent and deserves further research and development. At present, no report on enhancing sensitivity of salmonella to polymyxin by taking magnolol as a synergist is found at home and abroad.
Disclosure of Invention
The application aims at the application of magnolol as a polymyxin synergist in inhibiting salmonella, and the research of the application discovers that better inhibition effect can be achieved by combining with a specific culture medium in an in-vitro environment. According to the application, the survival rate of salmonella is taken as a target for screening the polymyxin synergist, and the survival rate of salmonella can be obviously reduced by screening Magnolol (MAG). In an in vivo test, by constructing a mouse salmonella intestinal tract infection model and combining MAG with colistin intraperitoneal injection, the salmonella quantity of feces, intestinal tracts, kidneys, livers and spleens can be reduced, and the survival rate of animals can be obviously improved.
The technical purpose is realized by the following scheme:
Use of magnolol in combination with polymyxin (CS) for the preparation of a medicament against salmonella infection.
Magnolol (MAG) is a hydroxylated biphenyl isolated from the root and stem bark of the plant, and has a wide range of biological activities such as muscle relaxation, antioxidant, anti-atherosclerosis, anti-inflammatory and antimicrobial effects. MAG has been reported to have a range of pharmacological actions including antioxidant, anti-inflammatory, antibacterial, antithrombotic or antiplatelet, anti-stress, anxiolytic, anti-Alzheimer's disease, anti-stroke, hypoglycemic, smooth muscle relaxant, weight control, anti-dyspepsia/prokinetic, anti-epileptic and liver-protecting effects.
Preferably, in an in vitro experiment, salmonella is first incubated to log phase, then incubated with LPM broth, diluted after incubation is completed, and then magnolol is added and colistin is combined.
Preferably, the salmonella is salmonella standard strain ATCC14028 and polymyxin-resistant salmonella.
Preferably, the concentration of the bacterial liquid after the incubation is 1X 10 6～5×106 CFU/mL.
Preferably, the pH of the LPM broth is 5.5 to 6.0.
Preferably, the concentration of magnolol is 50-400 mu M, and the concentration of polymyxin is 2-16 mg/L.
A combined culture method comprises culturing Salmonella, incubating to logarithmic phase, incubating with LPM broth, diluting after incubation, adding magnolol, and combining colistin. Preferably, the salmonella is salmonella standard strain ATCC14028 and polymyxin-resistant salmonella.
Preferably, the concentration of the bacterial liquid after the incubation is 1X 10 6～5×106 CFU/mL.
Preferably, the pH of the LPM broth is 5.5 to 6.0.
Preferably, the concentration of magnolol is 50-400 mu M, and the concentration of polymyxin is 2-16 mg/L.
In an in vivo test, by constructing a mouse salmonella intestinal tract infection model and combining MAG with colistin intraperitoneal injection, the salmonella amount of feces, intestinal tracts and spleens can be reduced, and the survival rate of animals can be obviously improved. The medicine is preferably in the form of injection, tablet, pill, capsule, suspension or emulsion.
Preferably, the dosage of polymyxin in the medicament is 5 mg/kg/day, and the dosage of magnolol is 5 mg/kg/day.
Compared with the prior art, the application has the beneficial effects that:
The application discovers that the magnolol and polymyxin have good synergistic effect on the experiment of salmonella in vitro and in vivo. Compared with the traditional method for killing salmonella by combining antibiotics and antibiotics, the synergistic sterilization of the plant-derived magnolol and polymyxin is not easy to induce the generation of bacterial drug resistance, and the magnolol has the characteristics of wide sources, low price and good treatment effect, and has good research and application significance for the synergistic substitution of the antibiotics and the solution of bacterial drug resistance.
Drawings
FIG. 1 shows a checkerboard heat map and in vitro sterilization curve of MAG in combination with polymyxin for Salmonella;
FIG. 2 shows a checkerboard thermal map of MAG in combination with polymyxin against Salmonella after cultivation in LB broth, based on example 1.
FIG. 3 shows a checkerboard thermal map of MAG in combination with polymyxin against Salmonella after MH broth culture, based on example 1.
FIG. 4 shows a checkerboard FICI bar graph of MAG in combination with polymyxin versus Salmonella after LPM, LB, MH broth culture based on example 1.
Figure 5 shows that MAG in combination with polymyxin significantly reduced the load of different tissue organs in salmonella-infected mice and significantly increased survival rate in mice.
Detailed Description
The technical solutions of the present invention will be clearly and completely described in conjunction with the embodiments of the present invention, and it is apparent that the described embodiments are only 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 test methods used in the examples of the present invention are conventional methods unless otherwise specified, and the materials, reagents, etc. used, unless otherwise specified, are commercially available reagents and materials.
The polymyxin used in the examples below is polymyxin E. The magnolol has CAS accession number 528-43-8, molecular formula of C 18H18O2 and molecular weight of 266.33.
The magnolol has the structural formula as follows:
example 1 magnolol enhances sensitivity of Salmonella to polymyxin in vitro
1. The autoclaved LPM broth at pH 5.8 was cooled for use. The standard strain ATCC 14028 of Salmonella, polymyxin-resistant Salmonella (17 ES) was stored in the laboratory and commercially available.
2. Preparation work before test:
(1) Preparing proper amount of MAG, wherein the solvent is dimethyl sulfoxide, the final concentration of the medicine is 200mM, and filtering with a filter membrane after uniformly mixing. Polymyxin was prepared as a stock solution at a concentration of 5120mg/L according to CLSI for use.
(2) The standard strain ATCC14028 of Salmonella and polymyxin-resistant Salmonella (17 ES) were inoculated onto LB agar plates and cultured to an appropriate size.
3. MIC and FICI of MAG and polymyxin for Salmonella
(1) The standard strain ATCC14028 of the test salmonella and the polymyxin-resistant salmonella (17 ES) are inoculated into a test tube filled with 4mLMH broth, and placed in a shaking table at 37 ℃ for 180rpm to be incubated to the logarithmic phase;
(2) Diluting the incubated bacteria to 100 times with LPM broth with pH of 5.8, about 10 6 CFU/mL for use;
(3) Taking a sterile 96-well plate, adding 180 mu L of LPM broth culture medium into a1 st well, and adding 100 mu L of LPM broth culture medium into 2 nd to 11 th wells respectively;
(4) Adding 20 mu L of medicine in column 1, blowing uniformly, sucking 100 mu L to the 2 nd hole, and then analogizing, and sucking 100 mu L from the 10 th hole for discarding;
(5) 100. Mu.L of diluted bacterial liquid is added to the 1st to 11 th wells, and 200. Mu.L of LPM broth culture broth is added to the 12 th wells;
(6) Repeating the steps (3) to (5) for three repeated parallelisms;
(7) Placing the inoculated 96-well plate into a 37 ℃ incubator for incubation for 16-18 hours, and reading the result;
(8) And according to the MIC result, performing a chessboard method. MAG concentration ranges from 6.25 to 400. Mu.M and polymyxin antibiotics effect concentrations range from 2 to 128mg/L.
MIC results are shown in Table 1, MIC values of MAG on standard bacteria of salmonella and polymyxin-resistant salmonella in LPM culture medium are more than 10mM, when MAG is combined with polymyxin, sensitivity of drug-resistant bacteria and standard bacteria on polymyxin can be obviously reduced, chessboard results are shown in FIG. 1, and chessboard results show that FICI is less than 0.5, so that MAG and polymyxin have good synergistic effect in treating salmonella.
TABLE 1
Furthermore, referring to steps (2) to (8) in MIC and FICI of MAG and polymyxin for Salmonella described above, the incubation effects of LB and MH media were compared, as shown in FIGS. 2 to 4, indicating that MAG combined with polymyxin was optimal for Salmonella after LPM broth culture.
4. In vitro sterilization curve of MAG and polymyxin on Salmonella
(1) The standard strain ATCC14028 of the test salmonella and the polymyxin-resistant salmonella (17 ES) are inoculated into a test tube filled with 4mLMH broth, and placed in a shaking table at 37 ℃ for 180rpm to be incubated to the logarithmic phase;
(2) Diluting the incubated bacteria to 10 times with LPM broth with pH of 5.8, about 10 7 CFU/mL for use;
(3) Adding 100-concentration MAG or polymyxin with antibacterial concentration into an LPM broth centrifuge tube with a pH value of 5.8, and then adding 0.4mL of diluted bacterial solutions obtained by diluting in the step (2) respectively, and mixing uniformly by vortexing for 5 s. A blank control group was set up as a quality control, and the control group was kept consistent with the test group except for the absence of drug. At this time, the concentration of the bacterial liquid is about 5X 10 6 CFU/mL, and the bacterial liquid is placed in a shaking table at 37 ℃ for culture at 180rpm, and the bacterial liquid system is 4mL;
(4) Taking bacterial liquid in the culture time of 0, 3,6 and 9 hours, sucking 100 mu L of bacterial liquid, adding the bacterial liquid into a 2mL centrifuge tube filled with 900 mu L of 0.85% physiological saline for 10 times of gradient dilution, sucking 25 mu L of bacterial liquid after dilution, dripping the bacterial liquid on MH agar culture medium, incubating the bacterial liquid in a 37 ℃ incubator for 18 hours, counting, and carrying out statistical analysis after the experimental result is subjected to three biological repetitions. The colony count at each time point was counted and a sterilization graph was drawn.
The results show that the in vitro sterilization curve of FIG. 1 shows that the bacterial load of MAG and polymyxin after being combined for 9 hours is reduced by more than 100 times compared with that of single medicine, and the synergy is remarkable, and the MAG and polymyxin combined has excellent effect of killing salmonella in vitro.
EXAMPLE 2MAG enhances the killing effect of polymyxin on Salmonella in vivo
1. Test materials 80C 57BL/6J female mice, mice stomach-filling needle, sterile syringe were purchased at university of medical science in south China, guangdong province.
2. Preparation before the test, 5mg/kg of polymyxin, 50mg/kg of MAG stock solution and 100000mg/L of streptomycin were prepared. Salmonella ATCC14028 strain was inoculated onto LB agar plates and cultured to an appropriate size. 9 mice per group, 4 total groups (control, polymyxin-treated, MAG-treated, combination).
3. Establishment of salmonella infection mouse model
(1) Each mouse was orally treated with 20mg of streptomycin and water cut run out of grain was performed 4 hours before treatment.
(2) After one day of streptomycin treatment, 100. Mu.L of ATCC14028 bacteria solution of about 10 8 was lavaged. The ATCC14028 strain to be tested was inoculated into a tube containing 4mL of LB broth, and incubated in a shaker at 37℃at 180rpm until the tube was removed from the logarithmic phase (about 10 8 cells).
4. Target organ colony colonization number detection after mouse infection
(1) 1 Day after infection of mice MAG (50 mg/kg, intraperitoneal injection, once a day) was administered singly and in combination with polymyxin (5 mg/kg, intraperitoneal injection, once a day).
(2) After continuous treatment with the above doses for 3 days, mice in the treatment group and quality control group were sacrificed by cervical dislocation, various organs were collected, and colony counts were performed.
As a result, the target organs (spleen, intestine, feces) of mice were significantly reduced after MAG in combination with polymyxin, compared to the best single-drug treatment group, and the bacterial load was reduced by more than 100-fold compared to single-drug treatment (see FIG. 5).
5. Treatment survival test after mice infection
(1) 1 Day after infection of mice MAG (50 mg/kg, intraperitoneal injection, once a day) was administered singly and in combination with polymyxin (5 mg/kg, intraperitoneal injection, once a day).
(2) After a sustained treatment with the drug dose of (1) for 7 days, mice survival curves of the treatment group and the quality control group were recorded and plotted.
The effects of significantly reducing the bacterial load in the animal feces after the combined treatment of MAG and polymyxin compared with the bacterial load after the combined treatment of the single drugs MAG and polymyxin in a mouse salmonella infection model are shown in the figure 5a, the effects of significantly reducing the bacterial load in the animal colon after the combined treatment of MAG and polymyxin compared with the bacterial load after the combined treatment of the single drugs MAG and polymyxin are shown in the figure 5b, the effects of significantly reducing the bacterial load in the animal spleen after the combined treatment of MAG and polymyxin compared with the bacterial load after the combined treatment of the single drugs MAG and polymyxin are shown in the figure 5c, and the effects of significantly increasing the survival rate of the animal after the combined treatment of MAG and polymyxin compared with the survival rate after the combined treatment of the single drugs MAG and polymyxin are shown in the figure 5 d.
Conclusion that after treatment day 7, the control group survived 11%, the MAG treated group survived 33%, the polymyxin treated group survived 44%, the MAG combined polymyxin survived 89% and the MAG combined polymyxin protecting rate was significantly higher than that of the polymyxin treated group (see FIG. 5). This suggests that the combination of MAG and polymyxin also has a good synergistic effect in the treatment of Salmonella infection in vivo.
In conclusion, the research takes the survival rate of salmonella as a target, and the natural product MAG and polymyxin are screened to have good in vitro killing effect on the salmonella. Finally, a salmonella infection mouse model is successfully established by oral infection of salmonella, and further, the combination of MAG and polymyxin can reduce colonial colonization of organs with different tissues and reduce death rate of mice infected with salmonella, and the researches provide ideas and foundation for the research and development of new medicines of polymyxin synergists.
It is apparent that the above examples of the present invention are only for clearly illustrating the technical solution of the present invention, and are not limited to the specific embodiments of the present invention. Any modification, equivalent replacement, improvement, etc. that comes within the spirit and principle of the claims of the present invention should be included in the protection scope of the claims of the present invention.
Claims (7)
1. The application of magnolol and polymyxin in combination in preparing medicine for resisting salmonella infection is provided.
2. The use according to claim 1, characterized in that said salmonella is salmonella standard strain ATCC14028 and/or polymyxin-resistant salmonella.
3. The use according to claim 1, wherein the polymyxin is polymyxin E.
4. The use according to claim 1, wherein the bacterial liquid concentration is 1 x 10 6～5×106 CFU/mL.
5. The use according to claim 3 or 4, wherein the concentration of magnolol is 50-400 μm and the concentration of polymyxin is 2-16 mg/L.
6. The use according to claim 1, wherein the medicament is in the form of an injection, a tablet, a pill, a capsule, a suspension or an emulsion.
7. The use according to claim 6, wherein the amount of polymyxin in the medicament is 5 mg/kg/day and the amount of magnolol is 5 mg/kg/day.
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2017005018A1 (en) * | 2015-07-09 | 2017-01-12 | 广州英赛特生物技术有限公司 | Use of substituted benzoguanidine derivative as polymyxin antibiotic synergist |
| CN110786424A (en) * | 2019-10-06 | 2020-02-14 | 湖北省农业科学院畜牧兽医研究所 | Application of magnolol and/or honokiol in poultry breeding |
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Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2017005018A1 (en) * | 2015-07-09 | 2017-01-12 | 广州英赛特生物技术有限公司 | Use of substituted benzoguanidine derivative as polymyxin antibiotic synergist |
| CN110786424A (en) * | 2019-10-06 | 2020-02-14 | 湖北省农业科学院畜牧兽医研究所 | Application of magnolol and/or honokiol in poultry breeding |
Non-Patent Citations (2)
| Title |
|---|
| YAN GUO ET AL.: "Honokiol Restores Polymyxin Susceptibility to MCR-1-Positive Pathogens both In Vitro and In Vivo", APPLIED AND ENVIRONMENTAL MICROBIOLOGY, vol. 86, no. 5, 31 March 2020 (2020-03-31), pages 2 * |
| 郭岩: "和厚朴酚的提取及增强多黏菌素对 mcr-1阳性菌的抗菌作用研究", 中国优秀硕士学位论文全文数据库 农业科技辑, no. 8, 15 August 2020 (2020-08-15), pages 17 * |
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