CN110215446B - Application of vanillic acid in inhibiting growth of multiple drug-resistant enterobacter cloacae - Google Patents
Application of vanillic acid in inhibiting growth of multiple drug-resistant enterobacter cloacae Download PDFInfo
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- CN110215446B CN110215446B CN201910614912.0A CN201910614912A CN110215446B CN 110215446 B CN110215446 B CN 110215446B CN 201910614912 A CN201910614912 A CN 201910614912A CN 110215446 B CN110215446 B CN 110215446B
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- A61K31/19—Carboxylic acids, e.g. valproic acid
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Abstract
The invention discloses an application of vanillic acid in inhibiting the growth of multiple drug-resistant enterobacter cloacae. The invention determines the drug resistance of the enterobacter cloacae to the antibiotics by using a paper diffusion method, determines the minimum bactericidal concentration of vanillic acid to the multidrug-resistant enterobacter cloacae to be 1.6mg/mL and the minimum bacteriostatic concentration to be 1.2mg/mL by using a double dilution method and an agar diffusion method, discloses that the non-antibiotic compound vanillic acid has an inhibition effect on the multidrug-resistant enterobacter cloacae, and has wide application value in the field of medicine.
Description
Technical Field
The invention relates to the field of medicines, in particular to application of vanillic acid in inhibiting growth of multiple drug-resistant enterobacter cloacae.
Background
Enterobacter cloacae is a bacterium of enterobacteriaceae widely existing in intestinal tracts of animals and human bodies, and is a common pathogenic bacterium for hospital acquired infection (Ningxingwang, Zhuhui, Congming, Sheer and soldiers, Qianjin 107 strains of enterobacter cloacae producing ESBLs and AmpC enzyme detection and drug resistance analysis [ J ]. practical preventive medicine, 2018,25(05): 534-. With the overuse and abuse of antibiotic drugs, the use of a large amount of immunosuppressive agents and chemotherapeutic drugs and various invasion, the clinical separation rate tends to increase, and the drug resistance rate also tends to increase, so that clinical drug-resistant strains including carbapenem-resistant antibiotics are increasing (Wang Fang, Wei ren Xiong, Zhang Xiao, Xianqing Qing, Zhou Tie Li, carbapenemase-producing vaginal canal rods, bacterial drug resistance characteristics and drug resistance gene analysis [ J ]. China J. Disinfection science, 2018,35(01): 17-19.).
The problem of bacterial drug resistance has been a global problem to be solved: common antibiotics continuously weaken the action of pathogenic bacteria, and even appear 'super bacteria'; the development of new chemical synthetic drugs with antibacterial activity is difficult and has long period. In the aspect of the problem of enhancing the drug resistance of bacteria, certain Chinese herbal medicines have antibacterial activity, have the advantages of rich resources, low adverse reaction, difficult generation of drug resistance and the like, and show unique advantages, so that the development of new antibacterial and antibacterial drug resistance medicines from the traditional Chinese medicines becomes a research hotspot.
Vanillic acid (4-hydroxy-3-methoxybenzoic acid, vanillic acid) is an oxidized form of vanillin, belonging to phenolic acids. The molecular formula is C8H8O4The molecular weight is 168.15, the CAS number is 121-34-6, the melting point is 208-210 ℃, and the molecular structure is:
vanillic acid is used as one of effective components of plants such as vanilla bean, vanilla pod and picrorhiza rhizome, is benzoic acid derivative used as flavoring agent in edible plants and fruits, and has certain pharmacological activity, such as antibacterial activity, anti-inflammatory activity, antioxidant activity, nerve regulating activity and procoagulant activity. There are currently few reports on the inhibition of bacterial growth by vanillic acid. The literature (Guo Xiaoyuan, Jing palace royal, Zhou Ruo Jun Fan. detection of phenolic acid content in decomposition liquid of corn straw and its influence on northern leaf blight [ J ]. corn science, 2016,24(04): 166) 172.) reports that vanillic acid can inhibit the growth of hypha of northern leaf blight, and the inhibition effect is enhanced with the increase of concentration. The inhibition of infectious calculus formation by vanillic acid was reported in the literature (Agnieszka Torzewska, Antoni Rozalski. inhibition of crystallization used by protein microorganisms during the course of the degradation of infectious urinary lipids by means of the basic substances of phthalic acids [ J ]. Microbiological Research,2014,169 (7-8)), and was compared with 2 conventional inhibitors of acetohydroxamic acid and pyrophosphate to find that vanillic acid inhibits bacterial growth. In vitro artificial urine studies have shown that vanillic acid at certain concentrations inhibits the formation of infectious calculi (plum bearing courage, herchuan, schshu, marshal, soil relay. intervention studies of vanillic acid in infectious calculi in rat urinary bladder [ J ]. Chinese drugs and clinics, 2019,19(05): 714-715.). However, there is no document reporting that vanillic acid has an inhibitory effect on multiple drug-resistant enterobacter cloacae.
Disclosure of Invention
The invention aims to provide the application of vanillic acid in inhibiting the growth of multiple drug-resistant enterobacter cloacae and provides a practical foundation for developing novel antibiotic substitutes.
In order to achieve the purpose, the invention adopts the technical scheme that:
determining the drug resistance of the enterobacter cloacae to antibiotics by using a paper diffusion method, and determining the minimum bactericidal concentration and the minimum bacteriostatic concentration of vanillic acid to the enterobacter cloacae by using a double dilution method and an agar diffusion method. The results show that: the non-antibiotic compound vanillic acid has a good bacteriostatic action on the multiple drug-resistant enterobacter cloacae and can be used for inhibiting the growth of the multiple drug-resistant enterobacter cloacae.
Preferably, the multidrug-resistant enterobacter cloacae is an enterobacter cloacae with multiple antibiotics of human sources resistant to cefazolin, cefotaxime, bromgertin, meropenem, ofloxacin, levofloxacin, ciprofloxacin, cefoxitin, minocycline, imipenem, piperacillin, azithromycin and nitrofurantoin.
Preferably, the vanillic acid has an inhibitory effect on enteric bacilli cloacae resistant to the antibiotics cefazolin, cefotaxime, bromgertin, meropenem, ofloxacin, levofloxacin, ciprofloxacin, cefoxitin, minocycline, imipenem, piperacillin, azithromycin and nitrofurantoin.
Preferably, the minimum bactericidal concentration of the vanillic acid is 1.6mg/mL, and the minimum bacteriostatic concentration is 1.2 mg/mL.
The invention has the beneficial effects that:
the invention starts from the existing medicinal plant resource library, excavates a potential drug-resistant bacteria inhibitor, utilizes vanillic acid to inhibit the growth of multiple drug-resistant enterobacter cloacae based on the action research of vanillic acid on the multiple drug-resistant enterobacter cloacae, provides a new idea for the research, development and application of the multiple drug-resistant enterobacter cloacae inhibitor, provides beneficial help for solving the drug resistance of antibiotics, and has wide application value in the field of medicine.
Furthermore, aiming at the difficult problem of clinical drug resistance, the invention utilizes the inhibiting effect of vanillic acid on the multiple drug-resistant enterobacter cloacae to be used as a substitute of antibiotics, can relieve or solve the problem of drug-resistant infection of the multiple drug-resistant enterobacter cloacae, and reduces the fatality rate.
Detailed Description
The present invention will be described in further detail with reference to examples. The examples are only for explaining the present invention and do not limit the scope of protection of the present invention.
1. Drug sensitivity test of enterobacter cloacae
The invention takes human source enterobacter cloacae as an initial strain (a strain sample is taken from Ningbo women hospital), and drug sensitivity tests are carried out by using 16 types of commonly used antibiotics such as cefazolin, cefotaxime, bromgertin, meropenem, ofloxacin, levofloxacin, ciprofloxacin, cefoxitin, minocycline, imipenem, piperacillin, azithromycin, nitrofurantoin, gentamicin and the like.
And (3) selecting and culturing the pure colonies for 18-24 hours, uniformly dissolving the pure colonies in 2-5 mL of sterile physiological saline, and adjusting the turbidity of the pure colonies to be equal to that of a 0.5 McLeod turbiditube. And (4) aseptically sucking 50-200 mu L of bacterial liquid, uniformly coating the bacterial liquid on a flat plate, and standing at room temperature for 3-5 min. Tightly attaching the drug sensitive test paper (diameter of 6mm) to the sterile forcepsOn the surface of the flat plate, three drug sensitive test paper sheets are parallel. And incubating the inoculated plate at 36-37 ℃ for 16-24 h. The diameter of the inhibition zone is measured by a vernier caliper with the precision of 0.02mm, the sensitivity of the human enterobacter cloacae to the drugs is judged according to the diameter of the inhibition zone, the inhibition result is judged according to the standard of the national standard administration committee of the clinical laboratory of the United states (CLSl2017), and the judgment standard is shown in the table 1. The results are shown in Table 2 and show that 1 strain of human Enterobacter cloacae (1)#Strain) can tolerate 13 clinically common antibiotics, so that the strain is taken as a research object of the next experiment.
TABLE 1 results of the national Committee for standardization management of the clinical laboratory (CLSl2017) standards
TABLE 2 diameter results of zone of inhibition in drug susceptibility test of human enterobacter cloacae
Note: the unit of the diameter of the inhibition zone in the table is mm, and the numerical values are the average values of three parallels
2. Inhibition of multiple drug-resistant strains by vanillic acid
In order to fully consider the medication safety, the invention takes vanillic acid single active ingredient as a research object, takes ATCC-13047 as a reference strain (purchased from the China center for quality inspection microbiological culture collection and sensitive to first-line antibiotics imipenem and meropenem) and takes 1#The strain is an experimental strain, and the drug resistance inhibition effect is researched. Selecting and culturing the pure bacterial colonies for 18-24 h, uniformly dissolving the pure bacterial colonies in 2-5 mL LB liquid medium, adjusting the turbidity of the pure bacterial colonies to be equal to that of a 0.5 McLeod turbiditube, and measuring the OD of the pure bacterial colonies by using a full-wavelength scanning multifunctional reading instrument600The value is obtained. Preparing 50mg/mL vanillic acid from dimethyl sulfoxide as a liquid medicine, adding the liquid medicine, a bacterial liquid and an LB liquid culture medium into a 96-hole culture plate by using a test tube double dilution method for overnight culture, wherein three liquid medicine groups with different concentrations are parallel, so that the reliability of experimental data is ensured.
The lowest concentration at which no bacteria grew at all (clear) in the 96-well plate was taken as the Minimum Inhibitory Concentration (MIC) of vanillic acid. On the basis of the minimum inhibitory concentration, the culture dishes are equally divided, 2 mu L of each suspension in the 96-well plate is dripped into a nutrient agar solid plate by using an agar diffusion method, and the plate is statically cultured for 24 hours at 37 ℃ to observe whether the bacterial colonies are generated. The lowest concentration of the liquid medicine without bacteria growth in the plate is the lowest bactericidal concentration (MBC) to the bacteria, and the experimental results are shown in Table 3.
TABLE 3 inhibition of multiple drug resistant Enterobacter cloacae by Vanillin
As shown in Table 3, the vanillic acid has a good inhibition effect on multi-drug resistant Enterobacter cloacae with 1.2mg/mL of MIC and 1.6mg/mL of MBC, which is resistant to cefazolin, cefotaxime, bromogematin, meropenem, ofloxacin, levofloxacin, ciprofloxacin, cefoxitin, minocycline, imipenem, piperacillin, azithromycin and nitrofurantoin. Although the MIC of vanillic acid to the reference strain is smaller than that of the multi-drug resistant strain, the vanillic acid also has an obvious inhibiting effect on the multi-drug resistant strain.
According to the experimental results, by combining the characteristics that the Chinese herbal medicines are not easy to generate drug resistance and the like, the active single component of the vanillic acid can be obtained to directly play an inhibiting role for the multiple drug-resistant enterobacter cloacae, so that the problems of drug resistance, infection, pathogenicity and the like of the multiple drug-resistant enterobacter cloacae can be effectively relieved or solved, the pathogenicity rate and the fatality rate are reduced, a new thought is provided for inhibiting the multiple drug-resistant enterobacter cloacae, and a solid foundation is laid for developing the inhibitor of the multiple drug-resistant enterobacter cloacae.
Claims (5)
1. Application of vanillic acid in preparing medicine for resisting multiple drug-resistant enterobacter cloacae is provided.
2. Use according to claim 1, characterized in that: the multiple drug-resistant enterobacter cloacae is human enterobacter cloacae.
3. Use according to claim 1, characterized in that: the multiple drug-resistant enterobacter cloacae is selected from enterobacter cloacae resistant to various antibiotics in cefazolin, cefotaxime, bromgertin, meropenem, ofloxacin, levofloxacin, ciprofloxacin, cefoxitin, minocycline, imipenem, piperacillin, azithromycin and nitrofurantoin.
4. Use according to claim 3, characterized in that: the minimum bactericidal concentration of the vanillic acid on the enterobacter cloacae is 1.6mg/mL, and the minimum bacteriostatic concentration is 1.2 mg/mL.
5. Use according to claim 1, characterized in that: the vanillic acid has an in vitro killing effect on the multiple drug-resistant enterobacter cloacae and inhibits the in vitro growth of the multiple drug-resistant enterobacter cloacae.
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Citations (2)
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| US20100191219A1 (en) * | 2009-01-27 | 2010-07-29 | Teleflex Medical Incorporated | Bacteriostatic Catheter Lock Containing Glycerol |
| WO2018222924A1 (en) * | 2017-06-01 | 2018-12-06 | Arizona Board Of Regents On Behalf Of Northern Arizona University | Antibiofilm formulations |
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Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20100191219A1 (en) * | 2009-01-27 | 2010-07-29 | Teleflex Medical Incorporated | Bacteriostatic Catheter Lock Containing Glycerol |
| WO2018222924A1 (en) * | 2017-06-01 | 2018-12-06 | Arizona Board Of Regents On Behalf Of Northern Arizona University | Antibiofilm formulations |
Non-Patent Citations (4)
| Title |
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| Antibacterial and Antioxidant Activities of Leaf Extracts from Juglans sinensis, and its Phenolic Compositions;Kook-Il Han等;《Natural Product Communications》;20171231;第12卷(第11期);第1797-1800页 * |
| Antiradical–antimicrobial activity and phenolic profile of pomegranate (Punica granatum L.) juices from different cultivars: a comparative study;Dimitra Z. Lantzouraki等;《RSC Advances》;20151231;第5卷;第2602-2614页 * |
| Characterization and Implications of Enterobacter cloacae Strains, Isolated from Italian Table Olives "Bella Di Cerignola";ANTONIO BEVILACQUA等;《JOURNAL OF FOOD SCIENCE》;20101231;第75卷(第1期);第M53-M60页 * |
| Chemosystematic Value of Chemical Constituents from Scabiosa hymettia(Dipsacaceae);Clio Christopoulou等;《CHEMISTRY & BIODIVERSITY》;20081231;第5卷;第318-323页 * |
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