CN114395026B - Broad-spectrum antibacterial peptide constructed based on rational design strategy - Google Patents
Broad-spectrum antibacterial peptide constructed based on rational design strategy Download PDFInfo
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- CN114395026B CN114395026B CN202210098946.0A CN202210098946A CN114395026B CN 114395026 B CN114395026 B CN 114395026B CN 202210098946 A CN202210098946 A CN 202210098946A CN 114395026 B CN114395026 B CN 114395026B
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- C07K14/46—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates
- C07K14/463—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates from amphibians
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/04—Antibacterial agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
- Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
- Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
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- General Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Oncology (AREA)
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- Genetics & Genomics (AREA)
- Gastroenterology & Hepatology (AREA)
- Molecular Biology (AREA)
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- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
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- Pharmacology & Pharmacy (AREA)
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Abstract
The invention discloses a broad-spectrum antibacterial peptide CA-1, the amino acid sequence of which is GLLSVLGSVAKHVLPHVVPVIAEHLWKKLFKK-NH 2 . The broad-spectrum antibacterial peptide is obtained by combining the related theoretical knowledge of the existing antibacterial peptide and modifying the natural antibacterial peptide Caerin1.1 from the Australian tree frog through rational molecular design. The antibacterial experiment result shows that the antibacterial peptide CA-1 has broad-spectrum antibacterial effect, has good inhibition effect on gram-positive bacteria and gram-negative bacteria, and the antibacterial concentration can reach 1-8 mug/ml. As determined by circular dichroism, the antibacterial peptide CA-1 has a negative absorption peak at 205-220 nm, and can form an alpha helix structure in TFE solution.
Description
Technical Field
The invention relates to a broad-spectrum antibacterial peptide CA-1, in particular to a broad-spectrum antibacterial peptide CA-1 obtained by taking natural antibacterial peptide Caerin1.1 derived from skin glands of Australian tree frog as a template and modifying the natural antibacterial peptide based on a rational design strategy on the basis of a certain theory, belonging to the technical field of biomedicine.
Background
1000 tens of thousands of people are expected to die from bacterial infection worldwide by 2050. Traditional antibiotics have remarkable effects on the aspect of treating bacterial infectious diseases, but due to the fact that people abuse the antibiotics, microorganisms generate stronger and stronger drug resistance on the traditional antibiotics, and the appearance of some superbacteria is more serious for public medical and health. Other antimicrobial approaches are urgently needed to alleviate the public health and medical puzzles of microbial resistance. The antibacterial peptide is considered as the most potential antibiotic substitute because of good antibacterial activity, broad-spectrum antibacterial effect, small molecular weight, simple structure, difficult generation of drug resistance and other excellent characteristics, and the antibacterial peptide is taken into the field of view of the public, so the research and development of the antibacterial peptide have very important significance.
The current mechanisms of action of antibacterial peptides can be largely divided into two types: one is interaction with a cell membrane, which is bound to the cell membrane by electrostatic interaction, to destroy the integrity of the cell membrane, leak the cell contents such as nucleic acids, proteins, ions, and the like, or hinder cell wall synthesis, and the like, and bacteria eventually die. Such as the well-known melatin, cecropin a. The other is to enter the inside of the cell through membrane permeation to destroy the normal physiological metabolism of the cell, and cause dysfunction and inactivate the cell. For example, the bee-derived antibacterial peptide Abaecin passes through the cell membrane when exerting antibacterial action, and enters the inside of the cell to be combined with DnaK and Hsp70 which affect protein folding and the biological functions of ribosome in the inside of the bacterial cell. The mechanism affects the normal physiological metabolism and business functions of bacterial cells, indirectly leads to the increase of the permeability of bacterial cell membranes and causes the death of bacteria, thereby exerting the antibacterial effect. It is because of the unique antibacterial mechanism of the antibacterial peptide that the antibacterial peptide is not easy to generate drug resistance.
By utilizing the difference of the cell membrane of the prokaryote and the eukaryote in the phospholipid composition, the antibacterial peptide has selective toxicity and can have toxic action on external pathogenic bacteria without damaging host cells. The peptidoglycan layer is thicker in the cell wall of gram-positive bacteria and contains negatively charged teichoic acid. The cell wall of gram-negative bacteria contains negatively charged Lipopolysaccharide (LPS), and both cell membranes contain negatively charged phospholipid substances such as Phosphatidylglycerol (PG), cardiolipin (CL) and Phosphatidylserine (PS). Is favorable for electrostatic interaction with positively charged antibacterial peptide, so that the antibacterial peptide can be adsorbed on the surface of bacteria. The phospholipid composition on the mammalian cell membrane is mainly electrically neutral Phosphatidylcholine (PC), phosphatidylethanolamine (PE) and Sphingomyelin (SM). The phospholipids are asymmetrically distributed, the phospholipids of the zwitterion are distributed on the outer layer, and the phospholipids with the negatively charged head groups are arranged in the outer layer and face the cytoplasm. It acts with antibacterial peptides mainly through hydrophobic interactions, which are weaker than electrostatic interactions. The surface of the membrane contains cholesterol which can keep the phospholipid bilayer stable. These factors are the basis of the selectivity of the antibacterial peptide, so that the antibacterial peptide has good antibacterial effect, and has little or no cytotoxicity to mammal cells in a certain concentration range.
Disclosure of Invention
Aiming at the defects of the prior art, the invention provides a broad-spectrum strong-effect antibacterial peptide CA-1 constructed based on a rational design strategy.
In order to achieve the above purpose, the invention adopts the following technical scheme:
the invention firstly provides a broad spectrumThe amino acid sequence of the antibacterial peptide CA-1 is as follows: gly-Leu-Leu-Ser-Val-Leu-Gly-Ser-Val-Ala-Lys-His-Val-Leu-Pro-His-Val-Val-Pro-Val-Ile-Ala-Glu-His-Leu-Trp-Lys-Lys-Leu-Phe-Lys-Lys-NH 2 Expressed in single letter as GLLSVLGSVAKHVLPHVVPVIAEHLWKKLFKK-NH 2 。
Furthermore, the broad-spectrum antibacterial peptide CA-1 is obtained by rational molecular design based on a natural antibacterial peptide Caerin1.1 from skin glands of Australian tree frog; wherein, the amino acid sequence of the natural antibacterial peptide Caninin 1.1 is: gly-Leu-Leu-Ser-Val-Leu-Gly-Ser-Val-Ala-Lys-His-Val-Leu-Pro-His-Val-Val-Pro-His-Val-Pro-Val-Ile-Ala-Glu-His-Leu-NH 2 Expressed in single letter as GLLSVLGSVAKHVLPHVVPVIAEHL-NH 2 。
Further, the broad-spectrum antibacterial peptide CA-1 has a molecular weight of 3543.34 and an electric charge of +4.
The invention also provides application of the broad-spectrum antibacterial peptide CA-1 in preparing broad-spectrum antibacterial drugs for treating gram-positive bacteria and gram-negative bacteria infection.
Specifically, the antibacterial peptide CA-1 has potent broad-spectrum antibacterial activity, and shows good antibacterial activity on 19 strains such as escherichia coli ATCC 8739, escherichia coli ATCC 25922, escherichia coli ATCC 8099, escherichia coli CMCC 44102, salmonella typhimurium CICC 51005, shigella flexneri CMCC 51571, vibrio parahaemolyticus ATCC 17802, pseudomonas fluorescens ATCC 13525, cronobacter sakazakii ATCC 29544, salmonella cholerae CICC 13312, staphylococcus aureus ATCC6538, staphylococcus aureus ATCC29213, staphylococcus aureus ATCC12600, staphylococcus aureus ATCC25923, staphylococcus aureus CMCC (B) 26003, methicillin-resistant staphylococcus aureus N315, bacillus cereus CMCC63301, micrococcus luteus CMCC28001, and bacillus pumilus CMCC 63202.
The invention has the advantages that:
according to the invention, natural antibacterial peptide Caerin1.1 from skin glands of Australian tree frog is used as a template, and is rationally designed and modified on the basis of a certain theory to obtain a brand new antibacterial peptide CA-1. The antibacterial peptide CA-1 contains 4 positively charged amino acids and 13 hydrophobic amino acids, has an absorption peak at 205-220 nm as determined by circular dichroism, and forms an alpha helix structure in TFE solution. The antibacterial peptide CA-1 can be combined with the hydrophobic region of phospholipid molecules in bacterial cell membranes due to strong hydrophobicity, so that the bacterial cell membranes are destroyed to play a role in sterilization.
Drawings
Fig. 1: helix pattern and three-dimensional structure pattern of antibacterial peptide CA-1 and Caerin 1.1. A, a helix structure diagram of Caninin 1.1; b, a spiral structure diagram of CA-1; c, a simulated three-dimensional structure diagram of the Caninin 1.1; d, simulation three-dimensional structure diagram of CA-1.
Fig. 2: high performance liquid chromatography of antibacterial peptide CA-1.
Fig. 3: liquid chromatography mass spectrometry of antibacterial peptide CA-1.
Fig. 4: circular dichroism spectrum of antibacterial peptide CA-1 in TFE solution.
Fig. 5: cytotoxicity of the antibacterial peptide CA-1 to Caco-2.
Detailed Description
In order to make the contents of the present invention easier to understand, the technical solutions of the present invention will be further described with reference to the specific embodiments, but the following examples are only examples of the present invention and do not represent the scope of the present invention defined by the claims.
Example 1
The invention modifies the natural antibacterial peptide Caerin1.1 on the basis of the existing theory so as to improve the antibacterial activity and reduce the cytotoxicity of the antibacterial peptide.
Calerin 1.1 is an antibacterial peptide separated from skin gland secretion mucus of Australian tree frog, and has charge of 0, high hydrophobicity of 0.734, and amino acid sequence of: GLLSVLGSVAKHVLPHVVPVIAEHL-NH 2 The proline residue at position 15/19 in this sequence has a great influence on the antibacterial activity of the antibacterial peptide, and can influence the alpha helix structure of the antibacterial peptide. The antibacterial peptide Caerin1.1 does not play a role in bacteriostasis through a membrane rupture mechanism, but passes through a cell membrane to destroy the physiology inside bacteriaThe process causes the bacteria to die, and has the sterilization effect. In previous studies, it was found that removal of the 5 amino acid sequence at the end of the antibacterial peptide calerin 1.1 did not affect the antibacterial activity of the antibacterial peptide calerin 1.1. Therefore, on the basis, a section of Cecropin A sequence (WKKLKK) is spliced on the original antimicrobial peptide Caerin1.1, cecropin A is a well-known peptide which plays a role in bacteriostasis through a membrane rupture mechanism, and the completely different bacteriostasis characteristics of the two peptides, namely the Canerin 1.1 and Cecropin A, are hoped to be combined, the membrane penetrating capacity of the antimicrobial peptide is improved on the basis of not damaging the original antimicrobial activity, a novel antimicrobial peptide CA-1 with stronger antimicrobial activity is designed, and certain properties of the antimicrobial peptide CA-1 are predicted through a plurality of prediction websites, such as physicochemical properties: antimicrobial Peptide Database-DBAASP, secondary structure: home|pbil (ibcp. Fr), spiral: https:// www.donarmstrong.com/cgi-bin/wheel. Pl, 3D structure prediction: the Yang Zhang Lab (zhanggroup. Org). The predicted results are as follows (table 1): from the physical and chemical property prediction results, the charge amount of the antibacterial peptide CA-1 is greatly improved compared with that of the antibacterial peptide CA-1; from the helix structural diagram (FIG. 1), the hydrophobicity of CA-1 is lower compared with that of Caerin1.1, but it can be seen that the reason for the reduced amphiphilicity is that the end-spliced fragments carry more charges, that is, one end of the antibacterial peptide CA-1 with the charges mainly concentrated, which can cause the antibacterial peptide CA-1 to be adsorbed on the bacterial cell membrane by electrostatic interaction at one end and destroy the bacterial cell membrane by hydrophobic effect at the other end, thereby enhancing the antibacterial effect. The predicted result shows that the secondary structure of the antibacterial peptide CA-1 is mainly an alpha helix structure, the two ends of the antibacterial peptide form an alpha helix structure, and the middle part is a random coil structure.
TABLE 1 prediction of physicochemical Properties of antibacterial peptide CA-1 and Caninin 1.1
Example 2
The antibacterial peptide CA-1 was synthesized by Jier Biochemical Co (Shanghai). The method adopts a solid phase chemical synthesis method, and the polypeptide passes through the reversed phase high-efficiency liquidPurifying by phase chromatography to purity of more than 95%, and further identifying amino acid sequence of polypeptide by electrospray mass spectrometry to obtain molecular weight 3543.34, and comparing the amino acid sequence prediction result with GLLSVLGSVAKHVLPHVVPVIAEHLKKFLKKW-NH of antibacterial peptide CA-1 2 And are consistent.
The chromatographic conditions are as follows: the chromatographic column was 4.6X 250mm,Kromasil C18 5um; liquid chromatography conditions: mobile phase: a pump: 0.1% by volume of acetonitrile trifluoroacetate solution, B pump: 0.1% by volume of aqueous trifluoroacetic acid. The flow rate is 1ml/min; the sample injection amount is 5 mu L; the detection wavelength is 220nm; elution time: 30min; the elution mode is gradient elution: the sample was introduced at the beginning at 36% A+64% B, at 25.0min at 61% A+39% B, at 25.1min at 100% A+0% B, and stopped when the sample was maintained for 30 min. The high performance liquid chromatogram of the antibacterial peptide CA-1 is shown in figure 2.
The mass spectrum conditions are as follows: mobile phase: water: acetonitrile = 1:1, nebulizer gas flow: 1.5L/min, sample injection amount: the CDL and Block temperatures were 250℃and 400℃respectively at 0.2 ml/min. The liquid chromatograph mass spectrum of the antibacterial peptide CA-1 is shown in figure 3.
Example 3
The secondary structure of the antibacterial peptide CA-1 was determined.
The secondary structure of the antibacterial peptide CA-1 was determined by circular dichroism. The antibacterial peptide CA-1 is dissolved in sterile water, and the sample and trifluoroethanol (Aladin) are mixed uniformly in a volume ratio of 1:1, so that the final concentration of the antibacterial peptide CA-1 is 128 mug/mL. The circular dichroism spectrum (190-250 nm) of the antibacterial peptide CA-1 was measured using a J-1500 electropolarimeter (Jasco, tokyo, japan), optical path 0.1cm, temperature 25℃and frequency 50nm/min. 3 replicates were measured. The results are shown in FIG. 4. The antibacterial peptide CA-1 forms a negative peak at 205-220 nm, and the CA-1 is in an alpha helix structure, which has great influence on the antibacterial activity.
Example 4
Antibacterial activity of the antibacterial peptide CA-1 is measured.
Determination of minimum inhibitory concentration (Minimum Inhibitory Concentration): the preparation method comprises selecting Escherichia coli ATCC 8739, escherichia coli ATCC 25922, escherichia coli ATCC 8099, and Escherichia coli CMCC 44102. Salmonella typhimurium CICC 51005, shigella flexneri CMCC 51571, vibrio parahaemolyticus ATCC 17802, pseudomonas fluorescens ATCC 13525, cronobacter sakazakii ATCC 29544, salmonella choleraesuis CICC 13312, staphylococcus aureus ATCC6538, staphylococcus aureus ATCC29213, staphylococcus aureus ATCC12600, staphylococcus aureus ATCC25923, staphylococcus aureus CMCC (B) 26003, methicillin-resistant Staphylococcus aureus N315, bacillus cereus CMCC63301, micrococcus luteus CMCC28001, bacillus pumilus CMCC63202, 19 strains as indicator bacteria. Inoculating the strains stored in the freezing tube into MHB liquid culture medium one by one for activation culture, culturing in shaking table at 37deg.C and rotation speed of 180r/min to logarithmic phase, transferring the above activated strains into fresh MHB liquid culture medium for secondary culture, shaking culture at 37deg.C in shaking table to logarithmic phase, and diluting strain culture solution cultured to logarithmic phase to 1×10 with fresh MHB liquid culture medium 5 cfu/ml for use.
Adding 90 mu l of MHB liquid culture medium and 10 mu l of 2560 mu g/ml antibacterial peptide CA-1 in the first column of a 96-well plate, adding 50 mu l of culture medium in 2-9 columns, uniformly mixing the 1 st column, sucking 50 mu l of mixed liquid of MHB liquid culture medium and CA-1 to the 2 nd column, continuously uniformly mixing the 2 nd column, removing 50 mu l of sample to the 3 rd column, and the like until the 9 th column; then, the diluted bacterial liquid was added to 2 to 9 columns in an amount of 50. Mu.l. Column 10 was added with 100. Mu.l MHB broth as a blank. Column 11 was added with 100. Mu.l of bacterial liquid as positive control.
Finally, the 96-well plate was placed in an incubator at 37℃for overnight incubation with slow shaking for 12 hours, and light absorption was measured at a wavelength of 600 nm. The minimum inhibitory concentration is the lowest sample concentration at which no bacterial growth is visible. The results are shown in Table 2.
According to the literature (FERNANDEZ D I, GEHMAN J D, SEPAROVIC F.membrane interactions of antimicrobial peptides from Australian frogs [ J ]. BBA-biomemembrane, 2009,1788 (8): 1630-1638.), the Australian tree frog antimicrobial peptide Caerin1.1 is a natural antimicrobial peptide with better antimicrobial activity against gram-positive bacteria (MIC value 4-12. Mu.g/ml for Staphylococcus aureus, 50. Mu.g/ml for Bacillus cereus) and weaker antimicrobial activity against gram-negative bacteria (MIC > 100. Mu.g/ml for Escherichia coli). As can be seen from Table 2, the antibacterial peptide CA-1 obtained by modification of the invention shows extremely strong antibacterial activity, the MIC for gram-positive bacteria is 2-4 mug/ml, the MIC for gram-negative bacteria is 1-8 mug/ml, and compared with the original antibacterial peptide Canin 1.1, the antibacterial activity of the antibacterial peptide CA-1 is obviously improved.
TABLE 2 antibacterial Activity of antibacterial peptide CA-1
Example 5
Cytotoxicity of the antibacterial peptide CA-1 was measured.
The cytotoxicity of the antibacterial peptide CA-1 is determined by adopting an MTT method, and the specific steps are as follows:
and (3) paving: digesting log-phase caco-2 cells with 0.25% pancreatin, washing with PBS buffer (0.01M, pH 7.2), centrifuging (2000 r/min, centrifuging for 3 min), collecting cells, preparing cell suspension, and regulating its concentration to 1×10 by cell counting method 5 Individual/ml; cell suspension was pipetted into 96-well plates (100. Mu.l/well) and placed in a cell incubator at 37℃under CO 2 Culturing for 24h under the conditions of 5% concentration and 95% humidity.
Sample adding: the prepared 96-well plate was removed from the incubator, the old cell culture medium was aspirated, and 90. Mu.l of fresh cell culture medium was added. Column 1 was added with 100. Mu.l PBS buffer (0.01M, pH 7.2) as a blank. Samples of the antibacterial peptide CA-1 were diluted with PBS buffer (0.01M, pH 7.2) to give concentrations of 128, 64, 32, 16, 8, 4, 2, 1. Mu.g/ml, 10. Mu.l sample per well, 5 groups were set in parallel for each concentration. The 96-well plate was then placed in an incubator for further incubation for 24 hours.
Adding MTT: to each well, 10. Mu.l of MTT at a concentration of 5mg/mL was added in the dark, and the culture was continued in an incubator for 4 hours.
The culture was terminated and crystals were dissolved: sucking out culture medium in the well plate, adding 150 μl dimethyl sulfoxide, incubating at 37deg.C and 600r/min in metal bath for 10min to dissolve the crystal, and detecting by ELISA OD 570 The absorbance of each well was measured at nm. The results are shown in FIG. 5.
SEQUENCE LISTING
<110> university of Fuzhou
<120> broad-spectrum antibacterial peptide constructed based on rational design strategy
<130>
<160> 2
<170> PatentIn version 3.3
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<212> PRT
<213> artificial sequence
<400> 1
Gly Leu Leu Ser Val Leu Gly Ser Val Ala Lys His Val Leu Pro His
1 5 10 15
Val Val Pro Val Ile Ala Glu His Leu Trp Lys Lys Leu Phe Lys Lys
20 25 30
<210> 2
<211> 25
<212> PRT
<213> artificial sequence
<400> 2
Gly Leu Leu Ser Val Leu Gly Ser Val Ala Lys His Val Leu Pro His
1 5 10 15
Val Val Pro Val Ile Ala Glu His Leu
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Claims (3)
1. A broad-spectrum antibacterial peptide CA-1, characterized in that: the amino acid sequence is as follows: gly-Leu-Leu-Ser-Val-Leu-Gly-Ser-Val-Ala-Lys-His-Val-Leu-Pro-His-Val-Val-Pro-Val-Ile-Ala-Glu-His-Leu-Trp-Lys-Lys-Leu-Phe-Lys-Lys-NH 2 Expressed in single letter as GLLSVLGSVAKHVLPHVVPVIAEHLWKKLFKK-NH 2 。
2. The broad-spectrum antibacterial peptide CA-1 according to claim 1, wherein: the broad-spectrum antibacterial peptide CA-1 is designed based on a natural antibacterial peptide Caerin1.1 from skin glands of Australian tree frog by rational molecular design, wherein the amino acid sequence of the natural antibacterial peptide Caerin1.1 is as follows: gly-Leu-Leu-Ser-Val-Leu-Gly-Ser-Val-Ala-Lys-His-Val-Leu-Pro-His-Val-Val-Pro-His-Val-Pro-Val-Ile-Ala-Glu-His-Leu-NH 2 Expressed in single letter as GLLSVLGSVAKHVLPHVVPVIAEHL-NH 2 。
3. The use of broad-spectrum antibacterial peptide CA-1 as claimed in claim 1 for the preparation of a broad-spectrum antibacterial medicament for the treatment of gram-positive and gram-negative bacterial infections.
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