CN103435686A - Polypeptide Cbf-14 resisting infection of drug-resistant bacteria and application thereof - Google Patents
Polypeptide Cbf-14 resisting infection of drug-resistant bacteria and application thereof Download PDFInfo
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Abstract
The invention relates to the field of biomedicine and in particular relates to an antibacterial polypeptide. Part of active amino acids of the antibacterial polypeptide of Cathelicidin family is mutated based on the antibacterial polypeptide of Cathelicidin family, and then the antibacterial polypeptide with high inhibitory activity to penicilin-resistant bacterium is obtained by solid phase chemical synthesis. The result of pharmacodynamic tests shows that the antibacterial polypeptide provided by the invention has good in vitro antibacterial activity and is applicable to treating diseases about drug-resistant bacterial infection.
Description
Technical field
The present invention relates to field of biomedicine technology, be specifically related to a kind of antimicrobial polypeptide and application thereof, antimicrobial polypeptide of the present invention has the purposes that the anti-drug resistance bacterium infects.
Background technology
Along with antibiotic extensive application, particularly aphalangia is taken over medicine for use, is selected standby antimicrobial drug, over-treatment irrelevantly and frequently change dressings, and causes the resistant rate of bacterium more and more higher, and drug-resistant intensity is more and more serious.The existence of spontaneous medicament-resistant mutation and the continuous action of antibiotic selective pressure, and the evolution of the adaptive capacity to environment of pathogenic bacteria and human body microenvironment ecologic change urges are the bases that resistant organism and multi-drug resistant bacteria produce clinically.Multi-drug resistant bacteria, broadly comprise extensive resistant organism or superbacteria, and its generation and development have brought huge challenge to clinical diagnosis and treatment.
Antibacterial peptide is a kind of very potential new antimicrobial agent source, and due to its unique Antibacterial Mechanism and various biological activity, so far, its research and application have become the focus in bio-pharmaceuticals and clinical medicine domain in research and development certainly.Compare advantages such as thering is molecular weight is little, has a broad antifungal spectrum, unique, the difficult generation resistance of Antibacterial Mechanism with traditional microbiotic.Cationic antibacterial peptide extensively is defined as is less than 50 amino acid whose polypeptide that are rich in positive ion, and half or above hydrophobic residue are arranged.The contained positive charge of polypeptide derives from Methionin and the entrained positive charge of arginine.Most of antibacterial peptide tool cationic and amphiphilic, because of the characteristic difference of the different polypeptide in position of length, charge number, aminoacid sequence and secondary structure.Polypeptide is divided into four classes according to its secondary structure, is respectively α spiral, β lamella, random coil and linear peptides.This peptide species has broad-spectrum bactericidal action, and gram-positive microorganism, Gram-negative bacteria and fungi are all produced effect.Some antibacterial peptides also have other physiologically actives, antiviral, anticancer, promote wound healing, activate immunity to reply etc.These characteristics of cationic polypeptide make it become the strong candidate of new medicine.The research of the mechanism of action of cationic antibacterial peptide is also more and more extensive.The mechanism of action of antibacterial peptide has a variety of, and some can make cytolemma thoroughly change, and some acts on cell walls, also has some to suppress macromolecular synthetic in cell.
But at present, there are three large bottlenecks in the development of antibacterial peptide, that is: the production cost of antibacterial peptide is high; The toxicity of antibacterial peptide is larger; The poor stability of antibacterial peptide to proteasome.Existing many scholar's research show can be from designing the structure of the original antibacterial peptide of improvement, retain its avtive spot, the reduction peptide chain, to reduce the production cost of antibacterial peptide.When carrying out the antibacterial peptide design, need to consider the factors such as toxicity and stability, itself and original natural antibacterial peptide are being consistent aspect toxicity and stability, by planning as a whole the factors such as electric charge, hydrophobicity, secondary structure, make its low toxicity efficient stable more.
Summary of the invention
The present invention is according to the antimicrobial polypeptide of Cathelicidin family, its part active amino acid site is suddenlyd change, adopt the solid state chemistry synthesis method to obtain the penicillin resistance bacterium is had to the high active antimicrobial polypeptide that suppresses, antimicrobial polypeptide of the present invention, aminoacid sequence is as shown in SEQ ID:NO:1.Be called for short Cbf-14, total order is classified as: arginine-Leu-Leu-arginine-Methionin-phenylalanine-phenylalanine-arginine-Methionin-leucine-Methionin-Methionin-Serine-α-amino-isovaleric acid.
Cbf-14 is by Cbf-K
16the C terminal amino acid carry out brachymemma, add α spiral tumor-necrosis factor glycoproteins simultaneously, adopt the solid state chemistry synthesis method to obtain bacterium and persister thereof had to high active 14 the amino acid whose antibacterial peptide mutant that have that suppress.After transformation, it contains 7 positive charges, and molecular weight is 1819.33, and iso-electric point is 12.31.The solid phase synthesis cost 2/3, therefore toxicity does not have considerable change, has greatly solved the high problem of production cost of antibacterial peptide, is conducive to the application of antibacterial peptide aspect the infection for the treatment of drug-resistant bacteria.
Adopt the solid state chemistry synthesis method can obtain antimicrobial polypeptide of the present invention.
Antibacterial activity in vitro research shows, peptide C bf-14 of the present invention has the effect of killing significantly drug tolerant bacteria, can be used to prepare the medicine that the anti-drug resistance bacterium infects.The preferred streptococcus aureus of described drug tolerant bacteria, staphylococcus epidermidis, escherichia coli, Pseudomonas aeruginosa and Klebsiella Pneumoniae.
Antibacterial peptide also likely acts on high organism and comprises human body cell in sterilization, because the mode of action of antibacterial peptide is all that perforation makes the death of cell generation seepage on cytolemma.So using antibacterial peptide can make red corpuscle generation seepage and antibacterial peptide can make the mouse primary splenocyte occur dead as whether a virose standard.If antibiotic Toplink makes the oxyphorase generation seepage in red corpuscle, just can be by detecting OD
540measure its toxicity size.Therefore the present invention has also detected the hemolytic activity of antibacterial peptide Cbf-14 of the present invention to sheep red blood cell (SRBC).Experiment shows, the hemolysis rate of antibacterial peptide of the present invention is very low.The present invention simultaneously finds that antibacterial peptide of the present invention does not have toxic action to mouse boosting cell in the experimental concentration scope.The result confirmation, the toxicity of antibacterial peptide of the present invention is minimum.
The accompanying drawing explanation
Fig. 1 is the HPLC collection of illustrative plates of antibacterial peptide Cbf-14 of the present invention
Fig. 2 is the Mass collection of illustrative plates of Cbf-14
Fig. 3 is the circular dichroism spectrum of Cbf-14
Fig. 4 is the killing curve of Cbf-14 to the streptococcus aureus of Penicillin-resistant
Fig. 5 is the killing curve of Cbf-14 to the staphylococcus epidermidis of Penicillin-resistant
Fig. 6 is the killing curve of Cbf-14 to the escherichia coli of Penicillin-resistant
Fig. 7 is the killing curve of Cbf-14 to the Pseudomonas aeruginosa of Penicillin-resistant
Fig. 8 is the killing curve of Cbf-14 to the Klebsiella Pneumoniae of Penicillin-resistant
Fig. 9 is the haemolysis curve of Cbf-14 to sheep red blood cell (SRBC)
Figure 10 is the toxicity of Cbf-14 to the mouse primary splenocyte
Embodiment
Embodiment 1
Synthetic and the structural identification of antimicrobial polypeptide Cbf-14:
Solid phase synthesis process synthetic polypeptide of the present invention routinely.Concrete experimental procedure is as follows:
The peptide sequence of the Cbf-14 of preparation is:
H-Arg-Leu-Leu-Arg-Lys-Phe-Phe-Arg-Lys-Leu-Lys-Lys-Ser-Val-OH
Synthesizing of polypeptide: the synthetic of polypeptide holds the N end to carry out one by one from C.Fmoc-Val-Wang Resin is soaked 15 minutes with methylene dichloride, treat that resin expands, and pumps methylene dichloride; Add the hexahydropyridine that volume ratio is 1:4/DMF solution, use nitrogen to agitate, react 2 times, the time is 5 minutes and 15 minutes, after reaction finishes, uses DMF washing resin 9 times.The resin that takes a morsel adds each 2-3 of toner ABC to drip (A liquid: triketohydrindene hydrate/ethanol solution; B liquid: pyridine; C liquid: phenol/ethanol solution) be total to heat 3 minutes under 100 ℃, solution and color of resin become blueness, to remove amido protecting.Add Fmoc-Val-OH and HOBT; with appropriate DMF, dissolve; add DIC and Collidine; nitrogen is agitated, and reacts 1 hour, after reaction finishes, uses DMF washing resin 6 times; repeat condensation reaction; connect successively each Fmoc protected amino acid, complete the synthetic of straight chain sequence, drain after resin is soaked with methylene dichloride and ether.Add TFA, react 2h in constant-temperature table, shaking speed 110r/min, 25 ℃ of temperature.The elimination resin adds anhydrous diethyl ether in filtrate, with the centrifugal rear acquisition solid of whizzer, adds the anhydrous diethyl ether washing, more centrifugal, repeats post-drying for several times and can obtain Cbf-14 crude product polypeptide.
Purifying: take a certain amount of crude product, add appropriate acetonitrile, ultrasonicly go out the macrobead magazine with strainer to clarification.Cross the preparative liquid chromatography instrument, sample is collected in segmentation simultaneously.Do gradient analysis with analytical chromatograph, will reach required purity sample and be retained.Then carry out the lyophilize processing.Polypeptide after purifying is identified through mass spectrum and high performance liquid chromatography.
By accompanying drawing 1, can be found out, polypeptide of the present invention, determine that by HPLC its purity is greater than 98.33%.
Can determine that by accompanying drawing 2 its molecular weight is respectively 1819.33, its molecular weight and theoretical value 1819.30 are coincide.
Use MOS450 circular dichroism spectrometer to measure the secondary structure of antibacterial peptide Cbf-14 under room temperature.Antibacterial peptide Cbf-14 concentration is 200 μ g/ml, and solution environmental is respectively Sodium dodecylbenzene sulfonate (SDS) and the trifluoroethanol (TFE) of pure water and 25mM.Sweep limit is 190～250nm, the quartz container of 0.1cm path length, and slit 1nm, sweep velocity is 100nm/min, each sample continuous sweep 3 times, average.The results are shown in Table 1 and accompanying drawing 3.
The secondary structure of table 1Cbf-14
In accompanying drawing 3 and table 1, can find out, Cbf-14 all is the random coil structure and exists in pure water.The SDS of 25mM is the micella peptide aggregation and exists in water, lipid bilayer that can the analog cell film.Cbf-14 has two smallest peaks at 208nm and 222nm place, and this is typical alpha-helix spectrogram.Cbf-14 is dissolved in TFE solution, the part α-helixstructure also occurs, but its principal mode is the beta sheet structure.The above results explanation Cbf-14 does not have stable conformation in the aqueous solution, but when their in conjunction with or approach cytolemma, during hydrophobic environment in contact membranes, can be induced into α-helixstructure and beta sheet structure.The alpha-helix of Cbf-14 in SDS is the highest, is secondly in TFE.
The drug effect of peptide C bf-14 of the present invention to the penicillin resistance bacterium:
(1) preparation of inoculum
To test and be connected to the nutrient agar medium inclined-plane with bacterium from the glycerine pipe, after 37 ℃ of overnight incubation, then picking a little be inoculated in the 2ml nutrient broth medium, cultivate 8h, with aseptic MH cultured solution of broth, be diluted to 10 for 37 ℃
5the bacterial suspension of CFU/ml left and right.
(2) configuration of medicine
Accurately take Cbf-14 and penicillin and be configured to the drug solution that concentration is 1024 μ g/ml, 0.22 μ m film sterile filtration, packing, put-70 ℃ of preservations standby.
(3) mensuration of minimal inhibitory concentration (MIC)
With aseptic MH cultured solution of broth, become 1ml to contain the solution that concentration is 512,256,128,64,32,16,8,4,2,1,0.5,0.25 μ g/ml medicine stoste doubling dilution.The above-mentioned bacterium liquid of getting 1ml adds in the pastille substratum prepared, and now, each test tube Chinese traditional medicine concentration is respectively 256,128,64,32,16,8,4,2,1,0.5,0.25,0.125 μ g/ml.Separately establish not the pastille group in contrast.Put in 37 ℃ of incubators and cultivate 16～20h, observe antibacterial effect, and record the MIC value.The results are shown in Table 2:
The MIC of table 2Cbf-14 to Penicillin-resistant bacterium and standard bacterium
As seen from Table 2, the selected drug-resistant bacteria of the present invention all reveals very strong resistance to penicillin, MIC to streptococcus aureus, staphylococcus epidermidis, escherichia coli, Pseudomonas aeruginosa, Klebsiella Pneumoniae all is greater than 256 μ g/ml, and Cbf-14 only has 16 μ g/ml to the MIC value of streptococcus aureus, staphylococcus epidermidis persister.MIC to escherichia coli and Pseudomonas aeruginosa is 32 μ g/ml.Result proves, Cbf-14 has the activity of certain resistance to penicillin resistant organism.
(4) mensuration of minimal bactericidal concentration (MBC)
Successively the above-mentioned culture of respectively managing that has no bacterial growth is drawn respectively to 0.1ml and is added in aseptic plate, with nutrient agar, mix, put 37 ℃ and cultivate 18h again, on plate, bacterium colony is less than the dilution drug level of minimum of 5 and is minimum bactericidal concentration MBC.The results are shown in Table 3:
The MBC of table 3Cbf-14 to Penicillin-resistant bacterium and standard bacterium
As can be seen from Table 3, antibacterial peptide of the present invention is about four times of MIC value to the MBC of Penicillin-resistant bacterium, and Cbf-14 is 16 μ g/ml to the MBC of streptococcus aureus, to the MBC of staphylococcus epidermidis and escherichia coli, is 64 μ g/ml.Cbf-14 to the MBC value of Pseudomonas aeruginosa and Klebsiella Pneumoniae at 128 μ g/ml.Penicillin does not have killing bacteria (MBC > 256 μ g/ml) in the experimental concentration scope.
(5) drafting of antibacterial peptide to the killing curve of Penicillin-resistant bacterium
Adopt the drug level of the MIC of 4 times, by prepare approximately 1 * 10
6the bacteria suspension of CFU/ml and medicament mixed, making its final concentration is 10
5the CFU/ml left and right.When 0min, 10min, 30min, 1h, 2h, 4h and 8h, draw the culture serial dilution, carry out live bacterial count, each extent of dilution is done three parallel laboratory tests, averages.Take the bacterial concentration logarithm as ordinate zou, and incubation time is X-coordinate, draws killing curve.Do blank and positive control simultaneously.The results are shown in accompanying drawing 1-5.
This experiment adopts the killing curve of the determination of drug concentration Cbf-14 of 4 * MIC to streptococcus aureus, staphylococcus epidermidis, escherichia coli, Pseudomonas aeruginosa and Klebsiella Pneumoniae.
By accompanying drawing 4, can be found out, Cbf-14 has good germicidal action to streptococcus aureus, and effect rapidly.Can kill all thalline in 10min.
By accompanying drawing 5, can be found out, Cbf-14 makes Resistant Staphylococcus epidermidis approximately 3 lgCFU that descended in 60min, and after 4h, bacterium is killed fully.As can be seen here, Cbf-14 is strong and quick-acting to the germicidal action of streptococcus aureus and staphylococcus epidermidis.
By accompanying drawing 6, can be found out, the sterilization effect effect of the escherichia coli that Cbf-14 is right is comparatively mild, and after 4 hours, killing curve tends to balance substantially, can basically kill all microorganisms.
By accompanying drawing 7, can be found out, Cbf-14 is similar to colibacillary effect to sterilization effect and the Cbf-14 of Pseudomonas aeruginosa, at 6h, can kill the penicillin resistant Pseudomonas aeruginosa fully.
By accompanying drawing 8, can be found out, Cbf-14 is mild to the Klebsiella Pneumoniae effect, at 6h, can basically kill the penicillin resistant Klebsiella Pneumoniae.
Antibacterial activity in vitro research shows, peptide C bf-14 has the effect of killing significantly drug tolerant bacteria, can be used to prepare the drug effect that the anti-drug resistance bacterium infects.The excellent finger of described drug tolerant bacteria streptococcus aureus, staphylococcus epidermidis, escherichia coli, Pseudomonas aeruginosa, Klebsiella Pneumoniae.
Embodiment 3
The toxicity of polypeptide antibacterial peptide Cbf-14 of the present invention, comprise that hemolytic mensuration reaches the eukaryotic cell toxicity test.
The hemolytic of polypeptide antibacterial peptide Cbf-14 of the present invention is measured:
With refrigerated centrifuge (4 ℃), by the centrifugal 10min of fresh Sheep Whole Blood 3000rpm, the sheep red blood cell (SRBC) obtained is washed three times with PBS, resuspended in the volume ratio by 10%.Medicine by resuspended sheep red blood cell (SRBC) equal-volume mixing gradient dilution, the final concentration that makes Cbf-14 is 512,256,128,64,32,16,8,4 and 2,1 μ g/ml, and establish the PBS group as negative control, 0.1%Triton X-100 group is as positive control, each gradient establish 6 parallel.All mixtures are put to 37 ℃ of incubators and hatch 1h.Use again afterwards the centrifugal 10min of refrigerated centrifuge (4 ℃) 3000rpm, get supernatant and 540nm wavelength and survey light absorption value.The results are shown in accompanying drawing 6.
Hemolysis rate=[(A540
cbf-14-A540
pBS)/(A540
0.1%Triton x-100-A540
pBS)] * 100.
The Sheep Blood cell is used to detect the hemolytic of antibacterial peptide Cbf-14, and the hemolytic of antibacterial peptide is considered to polypeptide to the Cytotoxic main criterion of mammalian blood.By accompanying drawing 9, can be found out, Cbf-14 is very low to the hemolytic of Sheep Blood cell, at the hemolysis rate of tested maximum concentration 512 μ g/ml, also only has 1%.Positive control 0.1%Triton X-100 hemolysis rate just reaches 100%.Result shows, Cbf-14 does not produce toxic action to the Mammals hemocyte in trial stretch.
The toxicity test of antibacterial peptide Cbf-14 of the present invention to splenocyte:
Get the spleen of healthy ICR mouse, through 300 purpose screen clothes, grind to form cell dispersion.With RPIM-1640(containing 10% calf serum) substratum is the resuspended one-tenth 5 * 10 of cell
7individual/ml, be placed in aseptic 96 orifice plates.The Cbf-14 medicine that simultaneously adds serial dilution, making its final concentration is 50,100,200,400,800,1600 μ g/ml, arrange simultaneously and make respectively negative control and positive control containing medicine group and ConA, each medicine gradient establish three parallel.Put CO
2incubator is cultivated and is hatched 48 hours.Then add MTT (5 μ g/ml), then after hatching 4 hours, through the centrifugal 10min of dull and stereotyped whizzer 3000rpm.Supernatant discarded, add DMSO and be dissolved in 490nm survey light absorption value, draws the cell toxicant curve.The results are shown in accompanying drawing 10.
By accompanying drawing 10, can be found out: along with the concentration increase of antibacterial peptide Cbf-14, light absorption value only has slight fluctuating, does not have significance increase or reduce.The significance increase does not occur or reduces in the splenocyte survival number that explanation is processed 48h through antibacterial peptide Cbf-14, and therefore, in the concentration range of experiment, Cbf-14 does not have toxicity to the splenocyte of mouse.
Sequence table
<110 > sea month bio tech ltd is reflected in Nanjing
<120 > the anti-drug resistance bacterium infects peptide C bf-14 and uses thereof
<130> 2013
<160> 1
<170> PatentIn version3.3
<210> 1
<211> 14
<212> PRT
<213 > artificial sequence
<400> 1
Arg Leu Leu Arg Lys Phe Phe Arg Lys Leu Lys Lys Ser Val
1 5 10
Claims (3)
1. an antimicrobial polypeptide, its aminoacid sequence is as shown in SEQ ID:NO:1.
2. a pharmaceutical composition, wherein contain antimicrobial polypeptide and the pharmaceutically acceptable carrier of claim 1.
3. the polypeptide of claim 1 is for the preparation of the purposes of anti-drug resistance bacterium infection medicine.
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Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103920137A (en) * | 2014-04-28 | 2014-07-16 | 中国药科大学 | Pharmaceutical composition having effect of resisting drug-tolerant gram positive bacteria |
| CN104971342A (en) * | 2015-07-13 | 2015-10-14 | 中国药科大学 | Pharmaceutical composition for resisting methicillin-resistant staphylococcus aureus (mrsa) |
| CN105031609A (en) * | 2015-07-22 | 2015-11-11 | 中国药科大学 | Disinfectant with antimicrobial peptides Cbf-14, and preparation and application of disinfectant |
| CN105497872A (en) * | 2015-12-23 | 2016-04-20 | 中国药科大学 | Medical application of polypeptide Cbf-14 in resistance to fungal infection |
| CN106543271A (en) * | 2016-12-08 | 2017-03-29 | 中国药科大学 | Anti-drug resistance infection peptide C bf 14 2 and application thereof |
| CN113480627A (en) * | 2021-06-25 | 2021-10-08 | 华中农业大学 | Antibacterial peptide and application thereof |
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| CN102702333A (en) * | 2012-05-29 | 2012-10-03 | 中国药科大学 | Drug-resistant pathogen infection resistant polypeptide and uses thereof |
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| CN102702333A (en) * | 2012-05-29 | 2012-10-03 | 中国药科大学 | Drug-resistant pathogen infection resistant polypeptide and uses thereof |
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Cited By (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103920137A (en) * | 2014-04-28 | 2014-07-16 | 中国药科大学 | Pharmaceutical composition having effect of resisting drug-tolerant gram positive bacteria |
| CN103920137B (en) * | 2014-04-28 | 2016-03-30 | 中国药科大学 | A kind of pharmaceutical composition with the effect of anti-drug resistance gram-positive bacteria |
| CN104971342A (en) * | 2015-07-13 | 2015-10-14 | 中国药科大学 | Pharmaceutical composition for resisting methicillin-resistant staphylococcus aureus (mrsa) |
| CN105031609A (en) * | 2015-07-22 | 2015-11-11 | 中国药科大学 | Disinfectant with antimicrobial peptides Cbf-14, and preparation and application of disinfectant |
| CN105031609B (en) * | 2015-07-22 | 2018-10-12 | 中国药科大学 | The disinfectant and its preparation and use of the Cbf-14 containing antibacterial peptide |
| CN105497872A (en) * | 2015-12-23 | 2016-04-20 | 中国药科大学 | Medical application of polypeptide Cbf-14 in resistance to fungal infection |
| CN106543271A (en) * | 2016-12-08 | 2017-03-29 | 中国药科大学 | Anti-drug resistance infection peptide C bf 14 2 and application thereof |
| CN106543271B (en) * | 2016-12-08 | 2019-07-30 | 中国药科大学 | Anti-drug resistance infects peptide C bf-14-2 and application thereof |
| CN113480627A (en) * | 2021-06-25 | 2021-10-08 | 华中农业大学 | Antibacterial peptide and application thereof |
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Denomination of invention: Antibiotic resistant bacterial infection polypeptide cbf-14 and its application Effective date of registration: 20220719 Granted publication date: 20150923 Pledgee: China Construction Bank Corporation Nanjing Gulou sub branch Pledgor: NANJING YINGHAIYUE BIOLOGICAL SCIENCE & TECHNOLOGY Co.,Ltd. Registration number: Y2022980010791 |
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