CN114539378B - Antibacterial peptide and application thereof in prevention and treatment of multiple drug-resistant bacteria - Google Patents
Antibacterial peptide and application thereof in prevention and treatment of multiple drug-resistant bacteria Download PDFInfo
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- 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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- A61P31/04—Antibacterial agents
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Abstract
The invention provides an antibacterial peptide and application thereof in preventing and treating multi-drug-resistant bacteria, the polypeptide has good antibacterial effect, and meanwhile, the antibacterial peptide and antibiotics are combined to kill the multi-drug-resistant bacteria. The amino acid sequence of the antibacterial peptide provided by the invention is SEQ ID NO. 1. The antibacterial peptide provided by the invention is used for preparing antibacterial products. The antibacterial peptide provided by the invention has obvious antibacterial effect on common pathogenic bacteria, and can effectively kill multi-drug resistant bacteria when being used in combination with antibiotics.
Description
Technical Field
The invention belongs to the technical field of application of antibacterial peptides, and particularly relates to an antibacterial peptide and application thereof in prevention and treatment of multiple drug-resistant bacteria.
Background
Overuse and abuse of antibiotics has led to the emergence of multi-drug resistant (MDR) bacteria. It is estimated that at present, infections caused by antibiotic-resistant bacteria cause about 7 tens of thousands of deaths worldwide each year, and infections caused by multi-drug resistant bacteria can cause an additional 1000 tens of thousands of deaths worldwide each year, exceeding cancer, by 2050 if no new treatment is available. Thus, antibiotic resistance has become an increasingly serious threat to public health of humans worldwide, and there is an urgent need to explore and develop new antibacterial strategies.
The two most promising strategies to solve this problem are the use of antibacterial peptides (antimicrobial peptides, AMPs) and combination therapies. AMPs are short peptides of 10 to 50 amino acids in length, naturally occurring from a variety of organisms including fungi, plants and animals, and were first isolated from human leukocyte extracts by Zeya and Spitznagel. AMPs, as part of the first line of defense of the host against pathogen invasion, exhibit broad antibacterial activity against various gram-positive and gram-negative bacteria, including MDR bacteria. Despite the high degree of amino acid sequence variation, most AMPs are amphiphilic, with cationic (positively charged) and hydrophobic properties that allow AMPs to efficiently interact with anionic microbial surfaces and enter the cell membrane, altering the membrane permeability and thus compromising internal homeostasis.
Combination therapy refers to the use of traditional antibiotics in combination with other antibiotics or AMPs to increase the therapeutic effect compared to monotherapy. Various conventional antibiotic combination therapies have become common treatments for multiple resistant bacterial infections, but the use of AMPs in combination with antibiotics has largely lacked extensive research.
Disclosure of Invention
The invention firstly provides an antibacterial peptide and application thereof in preventing and treating multi-drug resistant bacteria, the polypeptide has good antibacterial effect, and meanwhile, the antibacterial peptide and antibiotics are combined to kill the multi-drug resistant bacteria.
The amino acid sequence of the antibacterial peptide provided by the invention is as follows:
VFILSKYRWVMRFVPWCKALLKRFGKYKKHAK(SEQ ID NO:1)
the antibacterial peptide provided by the invention is used for preparing antibacterial products;
in a further aspect, the present invention provides an antimicrobial article comprising the above antimicrobial peptide and an antibiotic;
the antibiotics include Oxacillin (Oxacillin), vancomycin (Vancomycin), streptomycin (streptomycin), azithromycin (Azithromycin) and the like.
The antibacterial peptide provided by the invention has obvious antibacterial effect on common pathogenic bacteria, and can effectively kill multi-drug resistant bacteria when being used in combination with antibiotics.
Detailed Description
The present invention will be described in detail with reference to specific examples.
Example 1: screening and detection of antimicrobial peptides
An antibacterial peptide having an amino acid sequence of VFILSKYRWVMRFVPWCKALLKRFGKYKKHAK (SEQ ID NO: 1) was obtained by screening from chicken bursa of Fabricius and named AUDap. Through oxford cup experiments, the antibacterial peptide AUDAP has obvious antibacterial effect on gram-negative bacteria Escherichia coli strains (Escherichia coli) and gram-positive bacteria bacillus subtilis strains (Bacillus subtilis) without drug resistance; however, the antibacterial effect against Escherichia coli strain 577 (ATCC 577, E.coli 577) and Klebsiella pneumoniae strain Klebsiella pneumoniae 2182 (ATCC 2182,K.pneumonia 2182) having drug-resistant bacteria was not remarkable.
The Minimum Inhibitory Concentration (MIC) results of the AUDAP antimicrobial peptides against the four strains are shown in table 1.
Table 1: minimum inhibitory concentration values MIC (μg/mL) of AUDAP antibacterial peptide for four strains
Therefore, the AUDAP antibacterial peptide screened by the invention has antibacterial and bacteriostatic effects on gram-negative bacteria and gram-positive bacteria.
Example 2: cytotoxicity detection of AUDAP antibacterial peptides
The survival rate of the mouse macrophage cells under the action of the AUDAP antibacterial peptide is measured by an MTT colorimetric method, and the result shows that the AUDAP antibacterial peptide has no obvious toxic and damaging effect on RAW264.7 mouse macrophages under the condition of 15 mug/ml concentration, and the AUDAP antibacterial peptide has no obvious toxicity on normal tissue cells of mammals.
The method for determining the erythrocyte hemolysis of the antibacterial peptide AUDAP comprises the following specific steps:
1) Fresh mouse whole blood, heparin anticoagulated, centrifuged at 3000r/min for 10min at 4 ℃, and the pellet washed with physiological saline and resuspended at 8% (v/v);
2) mu.L of the red blood cell suspension was mixed with 100. Mu.L of the antimicrobial peptide solution at different concentrations. The mixed system is placed in a 37 ℃ incubator for incubation for 1h, taken out and centrifuged for 10min at 3000r/min at 4 ℃, the supernatant is taken out, and the absorbance at 570nm is measured by using an enzyme-labeled instrument.
The results show that the AUDAP antibacterial peptide of the invention only has hemolysis at the concentration of 75 mug/mL, which shows that the antibacterial peptide of the invention has almost no cytotoxicity to cells and can be developed into antibacterial drugs
Example 3: AUDAP antibacterial peptide and antibiotic combination
The strains examined were Escherichia coli 577 (ATCC 577, E.coli 577), klebsiella pneumoniae strain Klebsiella pneumoniae 2182 (ATCC 2182,K.pneumonia 2182) and methicillin-resistant Staphylococcus aureus strain USA500 (S.aureus USA 500).
AUDAP antibacterial peptide is synthesized by biological company, the carboxyl terminal is amidated during synthesis, and the purity of the synthesized product is more than 98%.
The synthesized AUDAP antibacterial peptide is dissolved in 1% (v/v) trifluoroethanol solution to prepare mother solution with the final concentration of 5mg/ml, and the mother solution is stored at the temperature of minus 80 ℃ for standby.
Inoculating strain to be detected into LB liquid medium, culturing, centrifuging to collect bacterial cells, repeatedly purging bacterial precipitate with PBS solution, re-suspending the obtained bacterial cells with PBS, counting with a blood cell counting plate under microscope, and diluting to a concentration of about 2×10 6 CFU/ml was used.
In order to detect the synergistic effect between AUDAP antibacterial peptide and antibiotics (vancomycin, streptomycin and azithromycin), a checkerboard trace dilution was performed using the method described by Sopirala et alAnd (5) releasing. The antibiotic peptide and the antibiotic are respectively diluted by LB as a double ratio, and the antibiotic peptide and the antibiotic with different concentrations are combined in a 96-well plate in a crossing way: leaving the concentration of antimicrobial peptide unchanged for each well in each row of a 96-well plate, 10 μl of antibiotic was added to give concentrations of 2×, 1×, 0.5×0, 0.25×1, 0.125×2, 0.0625×3, and 0.03125×4MIC in that order; the concentration of the antibiotic in each column of the 96-well plate was unchanged, 10. Mu.l of the antibacterial peptide solution was added to give a concentration of 2X, 1X, 0.5X, 0.25X, 0.125X, 0.0625X and 0.03125X MIC in this order, and the addition concentration of each well was 3X 10 6 CFU/ml bacterial liquid 10ul and 170ul fresh LB, set 3 parallel samples, shake uniformly, incubate at 37 ℃ for 10h. A PBS negative control group containing no antibiotic antibacterial peptide and a blank control group containing only LB medium were set. The minimum concentration without bacterial growth was the MIC at the time of combination, and absorbance at 600nm was measured under a multispan MK3 microplate reader to determine the MIC. The synergistic effect between the antibacterial peptide and the antibiotic uses the fractional inhibitory concentration Index FIC Index (FICI) method.
FICA = MIC for drug a combination/MI for drug a alone,
FICB = MIC for drug B combination/MIC for individual use,
FICI=FICA+FICB、
The synergistic effect is that the FICI is less than or equal to 0.5; the addition effect is that FICI is 0.5 less than or equal to 1; has no effect that FICI is 1 to 4; antagonism FICI >4.
The results show that the AUDAP antibacterial peptide and oxacillin treated S.aureus USA500 and the AUDAP antibacterial peptide and azithromycin treated K.pneumoniae 2182 have FICI less than or equal to 0.4 and all show synergistic antibacterial effect. The AUDAP antibacterial peptide and vancomycin have synergistic antibacterial effect on S.aureus USA500 and the AUDAP antibacterial peptide and streptomycin have synergistic antibacterial effect on E.coli 577, wherein the FIC is less than or equal to 0.5. When AUDAP antibacterial peptide and oxacilin were combined to treat S.aureus USA500, the concentration of AUDAP antibacterial peptide was reduced to 0.04×MIC. When the AUDAP antibacterial peptide is combined with vancomycin, the concentration of the AUDAP antibacterial peptide is reduced to 0.6XMIC.
The above results demonstrate that the AUDAP antibacterial peptide exhibits synergistic antibacterial effects against drug-resistant strains when combined with conventional antibiotics (oxacillin, vancomycin, streptomycin and azithromycin).
Sequence listing
<110> Qingdao university of agriculture
<120> an antibacterial peptide and its application in preventing and treating multiple drug-resistant bacteria
<160> 1
<170> SIPOSequenceListing 1.0
<210> 1
<211> 32
<212> PRT
<213> Artificial sequence (Artificial Sequence)
<400> 1
Val Phe Ile Leu Ser Lys Tyr Arg Trp Val Met Arg Phe Val Pro Trp
1 5 10 15
Cys Lys Ala Leu Leu Lys Arg Phe Gly Lys Tyr Lys Lys His Ala Lys
20 25 30
Claims (5)
1. The antibacterial peptide is characterized in that the amino acid sequence of the antibacterial peptide is SEQ ID NO. 1.
2. Use of the antibacterial peptide of claim 1 for the preparation of antibacterial products.
3. An antimicrobial preparation comprising a pharmacologically effective concentration of the antimicrobial peptide of claim 1.
4. The antimicrobial article of claim 3, further comprising an antibiotic.
5. The antimicrobial article of claim 4, wherein the antibiotic is any one or more of oxacillin, vancomycin, streptomycin, and azithromycin.
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Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN102807610A (en) * | 2012-09-05 | 2012-12-05 | 东南大学 | Antibacterial peptides and application of antibacterial peptides to preparation of medicament resisting drug-resistant bacteria |
CN112457413A (en) * | 2020-12-09 | 2021-03-09 | 青岛农业大学 | Method for expressing antibacterial peptide by SUMO fusion |
EP3932936A1 (en) * | 2019-02-28 | 2022-01-05 | Dandi Bioscience Inc | Polypeptide having antibacterial activity, composition for preventing or treating sepsis comprising same, and antibacterial composition |
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US11214594B2 (en) * | 2016-06-23 | 2022-01-04 | Konkuk University Industrial Cooperation Corp. | Antimicrobial peptide having synergistic antibacterial effect with antibiotics on multidrug resistant bacteria, and use thereof |
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Patent Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN102807610A (en) * | 2012-09-05 | 2012-12-05 | 东南大学 | Antibacterial peptides and application of antibacterial peptides to preparation of medicament resisting drug-resistant bacteria |
EP3932936A1 (en) * | 2019-02-28 | 2022-01-05 | Dandi Bioscience Inc | Polypeptide having antibacterial activity, composition for preventing or treating sepsis comprising same, and antibacterial composition |
CN112457413A (en) * | 2020-12-09 | 2021-03-09 | 青岛农业大学 | Method for expressing antibacterial peptide by SUMO fusion |
Non-Patent Citations (2)
Title |
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Tissue expression and antibacterial activity of host defense peptides in chicken;Mi Ok Lee等;《BMC Veterinary Research》;第12卷;231 * |
合生素和抗菌肽对肉仔鸡大肠杆菌病的防治效果及免疫调节;朱琪等;《中国畜牧兽医学会动物营养学分会第十二次动物营养学术研讨会论文集》;352 * |
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