CN109535238B - Structurally-modified antibacterial peptide Cec4 or salt thereof and application thereof - Google Patents
Structurally-modified antibacterial peptide Cec4 or salt thereof and application thereof Download PDFInfo
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Abstract
The invention provides an antibacterial peptide Cec4 with a modified structure or a pharmaceutically acceptable salt thereof, which is obtained by replacing one or more amino acids in the antibacterial peptide Cec4 by adopting an amino acid replacement mode, and proves that the antibacterial peptide Cec4 has stronger antibacterial performance and does not generate hemolysis, and the antibacterial active liquid is more stable under the conditions of salt ions with different concentrations and trypsin concentration. The sequence of the Cec4 is modified, the derived peptide is designed to verify the antibacterial performance of the derived peptide, and the correlation between the modification mode and the antibacterial activity is analyzed, so that an effective reference basis is provided for the subsequent optimization of the antibacterial peptide and the application of the antibacterial peptide in the preparation of antibacterial drugs.
Description
Technical Field
The invention belongs to the field of protein engineering, and particularly relates to an antibacterial peptide Cec4 with a modified structure or a salt thereof and application thereof in preparing a medicine for resisting gram-negative bacteria.
Background
Antibiotics are powerful weapons for treating diseases caused by bacterial infection, but the long-term overuse of antibiotics causes drug-resistant strains to replace sensitive strains to multiply greatly, so that the drug resistance rate of bacteria to the antibiotics is continuously increased. At present, a plurality of drug-resistant bacteria called superbacteria appear, and the drug-resistant bacteria seriously harm human health. Acinetobacter baumannii (Acinetobacter baumannii), a gram-negative bacterium which does not ferment sugars. In recent years, multiple drug-resistant and pan-drug-resistant acinetobacter baumannii have become more prevalent. In 2017, carbapenems-resistant acinetobacter baumannii is listed as the first key pathogen list of 13 types of antibiotics in urgent need by WHO. Therefore, there is an urgent need to develop novel antibacterial agents to cope with this dilemma. The antibacterial peptide (AMP) is an important component of an insect immune system, is a small molecular polypeptide with antibacterial activity in organisms, has the characteristics of small relative molecular mass, thermal stability, wide sterilization range, unique action mechanism and the like, is induced to generate the antibacterial peptide by infection or immune stimulation, is a natural barrier for defending invasion of pathogenic microorganisms, has strong antibacterial capability on bacteria, and has certain killing activity on fungi, viruses, tumor cells and the like. Therefore, antimicrobial peptides that do not easily cause bacterial resistance have become a hot spot for the development of novel antimicrobial drugs.
Previous studies found that housefly (Musca domestica) cecropin Cec4 has a good antibacterial effect on free acinetobacter baumannii (luo hui ling, yanggao, Penjian, etc.. the study on the antibacterial activity of acinetobacter baumannii by housefly cecropin Cec4 [ J ]. J. China microbiology and immunology, 2017, 37 (12): 891-896). Some engineered antibacterial peptides have been shown to have activity similar to or higher than the parent, and shortened peptide chains also reduce the cost of synthesis (Boman H.antibacterial and antibacterial properties of peptides which are protein targets of proteins-Letters, 1989,259(1): 103-106). By intercepting part of the peptide chain of cecropin CAl9 and efficiently expressing the cecropin CAl9 in escherichia coli, an antibacterial experiment shows that the peptide chain has stronger bacteriostatic activity (Yangmui, Wentan-an, Wanwhishu, etc.. the cecropin A truncated peptide has efficient expression and activity analysis in escherichia coli [ J ]. China J. antibiotics, 2010, 35(1), 20-23). Park (Park Y, Lee D G, Jang S H, et al, A Leu-Lys-rich antipicrobial peptide: activity and mechanism. Biochimica et Biophysica Acta,2013,1645(2):172-182.) and the like improve net positive charge and hydrophobicity by Lys substitution and Leu substitution, and 5 CA (1-8) -MA (1-12) analogues are designed, wherein amino acid residues at positions 4, 8, 14 and 15 are replaced by Lys and amino acid residues at positions 5, 6, 12, 13,16, 17 and 20 are replaced by Leu, and antibacterial activity and tumor inhibition activity of the CA-MA analogues are enhanced. The research shows that the cationic antibacterial peptide has too large or too small charge number which is not favorable for the combination of the antibacterial peptide and the cell membrane, and the hydrophobic residue, especially the C-terminal hydrophobicity, is kept in a certain range. Too high hydrophobicity results in aggregation of the antibacterial peptide itself, lowering of activity, and at the same time, improvement of hemolytic property, too low hydrophobicity results in lowering of membrane-inserting ability of the antibacterial peptide, and lowering of antibacterial activity (Xiajianhua, Zhao Wei, Wang rock, etc.. Synthesis of novel cationic antibacterial peptides and antibacterial activity thereof [ J ]. J. China J.Med.Industrials, 2016, 47 (3): 277-281). Thus, the major factors affecting the activity of the antimicrobial peptides include sequence, charge, amphiphilicity, hydrophobicity, PH, trypsin resistance, and the like. Therefore, it is necessary to structurally modify the Cec4 to improve its antibacterial activity.
Disclosure of Invention
The invention aims to provide an antibacterial peptide Cec4 with a modified structure so as to enhance the bacteriostatic activity of the antibacterial peptide, and an application of the antibacterial peptide Cec4 in preparing medicaments for resisting gram-negative bacteria.
In order to achieve the purpose, the invention adopts the following technical scheme:
a structurally modified antibacterial peptide Cec4 or a pharmaceutically acceptable salt thereof is obtained by replacing one or more amino acids in antibacterial peptide Cec4 by amino acid replacement. In addition to the antimicrobial peptide itself, the antimicrobial peptide of the present invention may also be combined with pharmaceutically acceptable salts, which also have the pharmaceutical effects thereof, including, but not limited to, salts with alkali metals or alkaline earth metals (such as sodium, potassium, calcium, or magnesium), and salts with the following inorganic acids: such as hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, and salts with organic acids, such as acetic acid, oxalic acid, succinic acid, tartaric acid, methanesulfonic acid, and maleic acid. The pharmaceutically acceptable salt is preferably a sodium salt.
Preferably, in the structurally modified Cec4 or the pharmaceutically acceptable salt thereof, the amino acid sequence of the structurally modified Cec4 is as shown in SEQ ID NO: 1. SEQ ID NO: 2 or SEQ ID NO: 3, respectively.
Preferably, in the structurally modified Cec4 or a pharmaceutically acceptable salt thereof, the amino acid sequence of the structurally modified Cec4 is as shown in SEQ ID NO: 3, respectively.
An antibacterial drug, the active ingredient of which is the antibacterial peptide or the pharmaceutically acceptable salt thereof. The above medicine can be made into various dosage forms such as injection, tablet, injectable sterile powder, granule, capsule, oral liquid, etc. The above-mentioned various dosage forms can be prepared according to the conventional method in the pharmaceutical field by using pharmaceutically acceptable carriers, and can be introduced into muscle, endothelium, subcutaneous, intravenous, mucosal tissue by injection, oral, physical or chemical mediated method, or introduced into the body after being mixed or coated with other substances.
The application of the structurally-modified antibacterial peptide Cec4 or the pharmaceutically acceptable salt thereof in preparing the anti-gram-negative bacteria medicament.
The structurally modified antibacterial peptide Cec4 or pharmaceutically acceptable salt thereof is applied to preparation of medicines for resisting acinetobacter baumannii and klebsiella pneumoniae.
Preferably, the structurally modified antibacterial peptide Cec4 or a pharmaceutically acceptable salt thereof is used for preparing an acinetobacter baumannii drug, wherein the acinetobacter baumannii is standard, multi-drug resistant or pan-drug resistant acinetobacter baumannii, and the klebsiella pneumoniae is standard, pan-drug resistant or multi-drug resistant klebsiella pneumoniae.
The invention has the beneficial effects that: the invention provides an antibacterial peptide Cec4 with a modified structure, which is obtained by replacing one or more amino acids in antibacterial peptide Cec4 by adopting an amino acid replacement mode, and proves that the antibacterial peptide Cec4 has stronger antibacterial performance, does not generate hemolysis phenomenon under higher concentration, and is more stable in antibacterial active liquid under the conditions of salt ions with different concentrations and trypsin concentration. The invention carries out sequence modification on Cec4, designs a derivative peptide to verify the antibacterial property of the derivative peptide, analyzes the correlation between the modification mode and the antibacterial activity, provides an effective reference basis for the subsequent antibacterial peptide optimization, and shows that the antibacterial peptide Cec4 with the modified structure obtained by the invention has greater application potential in the preparation of gram-negative bacteria resistant medicines, in particular to acinetobacter baumannii and klebsiella pneumoniae resistant medicines.
Drawings
FIG. 1 shows the hemolytic analysis of human erythrocytes by the Cec 4.
Detailed Description
The present invention will be further described with reference to the following examples.
1 materials and methods
1.1 materials
1.1.1 strains
Standard Acinetobacter baumannii (ATCC19606), Standard Klebsiella pneumoniae (ATCC700603) were stored in the etiological biology laboratory of Guizhou medical university, and multiple drug-resistant Acinetobacter baumannii (test No. 4367661), pan-drug-resistant Acinetobacter baumannii (test No. 4367992), multiple drug-resistant Klebsiella pneumoniae (test No. 4363617), and pan-drug-resistant Klebsiella pneumoniae (test No. 4367038) were collected from the Hospital affiliated to Guizhou medical university and stored in 25% glycerol at-80 ℃ in the dark.
1.1.2 antimicrobial peptides
A series of polypeptides are obtained by modifying the basic structure of the antibacterial peptide Cec4, the amino acid names and the sequences are shown in Table 1, and the chemical synthesis is carried out.
TABLE 1 names and sequences of amino acid substitution peptides of Cec4 (one letter code)
In Table 1, the amino acid substitution peptides of Cec4 were Cec4-1 (L at position 3 changed to R) (corresponding to SEQ ID NO: 1), Cec4-2 (W at position 2 changed to K) (corresponding to SEQ ID NO: 2), Cec4-3 (K at positions 39 and 41 changed to H), Cec4-4 (T at position 37 changed to F) (corresponding to SEQ ID NO: 3), Cec4-5 (ATI at positions 20, 21 and 22 changed to AGP), Cec4-6 (Q at position 30 changed to S), Cec4-7 (A at position 24 changed to V), and Cec4-8 (L at position 3 changed to V), respectively.
1.1.3 drugs and reagents
Sha's medium, agar powder purchased from Solarbio; peptone and yeast powder were purchased from OXOID; sodium chloride was purchased from Hengxing reagent Inc.; polymyxin B was purchased from Biosharp; 0.5 McLeod Boehringer was purchased from Beijing Tianan, United technology, Inc.
1.1.4 Instrument
Milli-Q ultra pure water instruments (Millipore PHarmacia, France); autoclave (japanese ALR); model PB203-E electronic precision balance (shanghai mettlettoduo instruments corporation); digital display stainless steel electrothermal incubator (Shanghai Boxun practice) of micro sample applicator (Eppendorf Co., Germany); centrifuge (Sigma1-15 high speed bench centrifuge, Sigma, Germany); clean bench (suzhou clean equipment limited); microplate reader (Biotech Epoch 2, BioTeck, USA).
1.2 methods
1.2.1 design of amino acid substitutions with Cec4
Since the biological activity of cecropin-type antibacterial peptides is affected by various physical, chemical and steric structures such as net positive charge, hydrophobicity, alpha helix structural stability, helicity and hinge structure. Therefore, the charge quantity and the hydrophilicity and hydrophobicity of the parent peptide Cec4 are changed by amino acid substitution in the invention.
1.2.2 antimicrobial Spectrum screening and MIC value determination
Taking logarithmic growth Acinetobacter baumannii and Klebsiella pneumoniae, diluting the Acinetobacter baumannii and Klebsiella pneumoniae to 1.0 x 10 by using MH culture medium6cfu/mL, adding bacterial liquid and antibacterial peptide Cec4 with different concentrations and modified peptide thereof into each hole of a 96-hole plate as an experimental group, taking polymyxin B as a positive control, taking the bacterial liquid as a negative control, culturing the bacterial liquid at 37 ℃ and 120rpm for 24h, and referring to the judgment standard of a liquid dilution method in the American Clinical Laboratory Standards Institute (CLSI), wherein the lowest concentration of the drug, at which bacteria growth is not seen with naked eyes, is the Minimum Inhibitory Concentration (MIC) of the bacteria to be detected.
1.2.3 influence of salt ion concentration and trypsin antibacterial peptide Cec4 on the antibacterial activity of the modified peptide: collecting drug-resistant Acinetobacter baumannii growing in logarithmic phase, and diluting to 1.0 × 10 in MH culture medium6cfu/mL. After adding different concentrations of Cec4 and its modified peptide to 96-well plates, mixing with different concentrations of salt ion concentration and trypsin, and culturing with Acinetobacter baumannii at 37 ℃ and 120rpm for 24h, and observing the results.
2 results and analysis
2.1 in vitro antibacterial activity test of amino acid substitution peptide Cec4 the data in Table 2 show that the MIC value of Cec4 to different drug-resistant strains is within the range of 4-8 mug/mL, and the MIC value of amino acid substitution peptide Cec4-4 to different drug-resistant strains is within the range of 2-4mg/L, which indicates that the peptide has stronger antibacterial property and different drug-resistant strains have different sensitivities. The amino acid substitution peptides Cec4-3, Cec4-5 and Cec4-8 have no antibacterial activity, and indicate that the substituted amino acid is the essential amino acid for the activity to play.
TABLE 2 MIC of the Cec4 amino acid substitution peptide for various strains
Note: standard Ab is Standard Acinetobacter baumannii; pan-resistant Ab is Pan-drug-resistant acinetobacter baumannii;
the Multidrug-resistant Ab is multiple drug-resistant Acinetobacter baumannii; standard Kp is Standard Klebsiella pneumoniae;
pan-resistant Ab is Pan-drug resistant Klebsiella pneumoniae; the Multidrug-resistant Ab is Multidrug-resistant Klebsiella pneumoniae.
2.2 hemolytic assay
In the experiment, as the concentrations of the antibacterial peptides Cec4 and Cec4-4 are gradually increased to 1mg/mL, the hemolysis rates are less than 5%, and the hemolysis phenomenon is shown to be no, which indicates that the antibacterial peptides Cec4 and Cec4-4 are safe for human bodies in the aspect of hemolysis, and the result is shown in the hemolysis analysis of the antibacterial peptide Cec4 of the figure 1 on human erythrocytes. The judgment standard refers to the judgment standard of hemolysis experiment in the test method of medical transfusion, blood transfusion and injection apparatus (Chinese national Standard administration Committee GB/T14233.2.2005 test method for medical transfusion, blood transfusion and injection apparatus [ S ]. Beijing: Chinese Standard Press, 2005: 6-7), the hemolysis rate is less than 5 percent, the reaction is negative, and no hemolysis phenomenon exists; the hemolysis rate is more than 5%, and the hemolysis phenomenon is shown.
2.3 effect of salt ionic strength on Cec4 engineered peptide antibacterial activity: cationic antimicrobial peptides cause perforation of cell walls and membranes by interacting with negatively charged outer cell walls, eventually leading to bacterial death. The presence of various ions in the solution can cause changes in the charge of the antimicrobial peptide, thereby affecting its antimicrobial activity. The experimental results show that the antibacterial activity of the antibacterial peptides Cec4 and Cec4-4 is not affected with the increase of the salt ion strength (0-200 mM), which indicates that the antibacterial activity of the antibacterial peptides Cec4 and Cec4-4 is stable under the condition of different salt ion concentrations (Table 3).
TABLE 3 Effect of salt ion concentration on Cec4 bacteriostatic Activity
Note: "+" indicates that there is bacterial growth; "-" represents no bacterial growth
2.4 effects of trypsin concentration on Cec4 and engineered peptides antibacterial activity: oral antibacterial drugs are common administration modes, and trypsin in gastric juice has the capability of carrying out protein enzymolysis, so that the primary structure of antibacterial peptide is damaged, the amino acid composition is changed, and the antibacterial activity is reduced. After the action of high-concentration trypsin (0.5mg/mL and 1.0mg/mL) and different concentrations of antibacterial peptides Cec4 and Cec4-4(0, 2, 4 and 8 mu g/mL), the results show that the concentration of Cec4 and Cec4-4 is 4 mu g/mL under the action of 0.5mg/mL of trypsin, both of which have antibacterial activity; when the concentration of trypsin is increased to 1.0mg/mL, the concentration of Cec4 is 8 mug/mL, and the concentration of Cec4-4 is 4 mug/mL, the antibacterial activity is realized, which shows that when the concentration of trypsin in the solution is 1-7 times of the physiological concentration, Cec4-4 still has certain stability (Table 4).
TABLE 4 Effect of Trypsin on Cec4 and modified peptides bacteriostatic Activity
Note: "+" indicates that there is bacterial growth; "-" represents no bacterial growth
Not all amino acid sequences in natural antimicrobial peptides are necessary for their antimicrobial function, and purposefully selecting specific sites of peptide chains or deleting unrelated sequences, so as to obtain effective short peptides is a common method for molecular design of antimicrobial peptides (suqinghong, xu dao, royal shiru. molecular design research on antimicrobial peptides progress [ J ] chemical and biological engineering, 2012, 29 (11): 1-4). The amino acid substitution method is adopted to modify housefly cecropin Cec4, and the influence of hydrophilicity and hydrophobicity and charge change on the antibacterial activity of Cec4 is researched. Wherein the amino acid substituted by the sequences Cec4-3, Cec4-5 and Cec4-8 is the key amino acid of Cec4 which plays the bacteriostatic activity, and the bacteriostatic activity disappears after the original amino acid is substituted; although the Cec4-1 and Cec4-2 can inhibit the growth of strains, the activity is inferior to that of Cec4, which shows that the activity of Cec4 cannot be enhanced by increasing the hydrophilicity and the charge quantity of an N end, and the antibacterial activity is proved to be increased along with the increase of the number of positive charges in a certain range but not increased all the time, when the number of the positive charges exceeds a certain critical value, the electrostatic repulsion among antibacterial peptide molecules is enhanced, the electrostatic attraction with a membrane is enhanced, the aggregation of the antibacterial peptide molecules on the membrane and the formation of membrane-penetrating pore channels are hindered, and finally, the antibacterial activity is reduced as the membrane cracking capability. The modified peptide Cec4-4 enhances the hydrophobicity of the C end by 1 time on the basis of Cec4, the charge number is unchanged, the antibacterial activity is similar to that of Cec4, the antibacterial activity of the modified peptide against acinetobacter baumannii is greater than that of Cec4, and the activity enhancement may be related to the increase of the hydrophobicity of the C end, so that the structural composition of an amphoteric molecule is changed. In addition, the hemolytic property of the drug is an important index for judging the safety of the drug, and experiments show that the antibacterial peptides Cec4 and Cec4-4 do not cause hemolysis within the experimental dosage range. The antibacterial activity of Cec4 and Cec4-4 was not affected at high salt ion strength. When the trypsin is at a high physiological concentration of 0.5mg/mL, the antibacterial activity of Cec4 and Cec4-4 is stable, but when the trypsin is increased to 1mg/mL, Cec4-4 has better trypsin resistance than Cec 4.
The invention carries out sequence modification on Cec4, designs a derivative peptide to verify the antibacterial property of the derivative peptide, analyzes the correlation between the modification mode and the antibacterial activity, provides an effective reference basis for the subsequent antibacterial peptide optimization and the application in the preparation of antibacterial drugs, and shows that the antibacterial peptide Cec4 which is obtained by the invention and is subjected to structure modification has greater application potential in the preparation of the antibacterial drugs against gram-negative bacteria, in particular to the medicines against acinetobacter baumannii and the medicines against klebsiella pneumoniae.
Sequence listing
<110> Guizhou medical university
<120> antibacterial peptide Cec4 with modified structure and application thereof
<160> 3
<170> SIPOSequenceListing 1.0
<210> 1
<211> 41
<212> PRT
<213> Artificial sequence (unknown)
<400> 1
Gly Trp Arg Lys Lys Ile Gly Lys Lys Ile Glu Arg Val Gly Gln Asn
1 5 10 15
Thr Arg Asp Ala Thr Ile Gln Ala Ile Gly Val Ala Gln Gln Ala Ala
20 25 30
Asn Val Ala Ala Thr Leu Lys Gly Lys
35 40
<210> 2
<211> 41
<212> PRT
<213> Artificial sequence (unknown)
<400> 2
Gly Lys Leu Lys Lys Ile Gly Lys Lys Ile Glu Arg Val Gly Gln Asn
1 5 10 15
Thr Arg Asp Ala Thr Ile Gln Ala Ile Gly Val Ala Gln Gln Ala Ala
20 25 30
Asn Val Ala Ala Thr Leu Lys Gly Lys
35 40
<210> 3
<211> 41
<212> PRT
<213> Artificial sequence (unknown)
<400> 3
Gly Trp Leu Lys Lys Ile Gly Lys Lys Ile Glu Arg Val Gly Gln Asn
1 5 10 15
Thr Arg Asp Ala Thr Ile Gln Ala Ile Gly Val Ala Gln Gln Ala Ala
20 25 30
Asn Val Ala Ala Phe Leu Lys Gly Lys
35 40
Claims (5)
1. A structurally modified antibacterial peptide Cec4 or a pharmaceutically acceptable salt thereof is characterized in that the antibacterial peptide Cec4 or the pharmaceutically acceptable salt thereof is obtained by replacing one or more amino acids in antibacterial peptide Cec4 by adopting an amino acid replacement mode; the amino acid sequence of the antibacterial peptide Cec4 after structural modification is shown as SEQ ID NO: 3, respectively.
2. An antibacterial agent characterized in that the active ingredient thereof is the antibacterial peptide according to claim 1 or a pharmaceutically acceptable salt thereof.
3. Use of the structurally engineered antibacterial peptide Cec4 or a pharmaceutically acceptable salt thereof of claim 1 in the preparation of a medicament against gram-negative bacteria.
4. The use of the structurally modified Cec4 or the pharmaceutically acceptable salt thereof according to claim 1 for preparing anti-acinetobacter baumannii and anti-klebsiella pneumoniae drugs.
5. The use of the modified Cec4 or its pharmaceutically acceptable salt according to claim 4, in the preparation of anti-acinetobacter baumannii and anti-klebsiella pneumoniae drugs, wherein the acinetobacter baumannii is standard, multi-drug resistant or pan-drug resistant acinetobacter baumannii, and the klebsiella pneumoniae is standard, pan-drug resistant or multi-drug resistant klebsiella pneumoniae.
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1365981A (en) * | 2001-01-19 | 2002-08-28 | 山东大学 | Antibacterial peptide gene of fly and its cloning process |
| CN106366172A (en) * | 2016-10-17 | 2017-02-01 | 黑龙江八农垦大学 | Bigeminal peptide Cec Md2ys, preparation method and application |
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- 2018-12-18 CN CN201811546382.2A patent/CN109535238B/en active Active
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1365981A (en) * | 2001-01-19 | 2002-08-28 | 山东大学 | Antibacterial peptide gene of fly and its cloning process |
| CN106366172A (en) * | 2016-10-17 | 2017-02-01 | 黑龙江八农垦大学 | Bigeminal peptide Cec Md2ys, preparation method and application |
Non-Patent Citations (1)
| Title |
|---|
| Efficacy of designer K11 antimicrobial peptide (a hybrid of melittin, cecropin A1 and magainin 2) against Acinetobacter baumannii-infected wounds;Praveen Rishi等;《Pathogens and Disease》;20181031;第76卷(第7期);1-8 * |
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