An antibacterial cyclic peptide and compositions thereof, and methods of making and use

Abstract

The application discloses an antibacterial cyclic peptide, a composition of the antibacterial cyclic peptide, a preparation method and application, and an amino acid sequence of the antibacterial cyclic peptide is shown as formula (I). The antibacterial cyclic peptide is added into corresponding adjuvant to prepare the composition. Experiments prove that the antibacterial cyclic peptide has good antibacterial activity, and has good application prospect in preparation of medicines.

Description

TECHNICAL FIELD

[0001] The present application relates to the technical field of biological medicine, in particular to an antibacterial cyclic peptide and a composition thereof, a preparation method and an application. BACKGROUND

[0002] The statements in this section merely provide background information related to the present disclosure and can not constitute the prior art.

[0003] Antibiotics are mainly secondary metabolites produced by bacteria, molds or other microorganisms or artificial analogues. Antibiotic drugs are widely used in various infectious diseases, and the excessive use of traditional antibiotics in clinical practice has produced many medically relevant drug-resistant strains.

[0004] Cationic antibacterial peptides can represent a new type of antibiotic. Although the mode of action of cationic antibacterial peptides has not been fully determined, all cationic amphiphilic antibacterial peptides interact with cell membranes. Cell membranes are the main target of antibacterial peptides, and the aggregation of antibacterial peptide molecules on the cell membrane leads to an increase in cell membrane permeability, resulting in the loss of barrier function of the cell membrane. Microorganisms produce such drug resistance mainly based on the formation of bacterial biofilms, which creates a penetration barrier for drugs, limits nutrients and changes gene phenotypes, and antibacterial peptides have good antibiofilm activity and can inhibit and eliminate biofilms. Therefore, antibacterial peptides targeting biofilm activity have little chance of causing microorganisms to develop drug resistance.

[0005] Alpha-helical and beta-sheet antibacterial peptides are the two main types of cationic antibacterial peptides. Beta-sheet antibacterial peptides include ring-shaped polypeptides fixed by intramolecular disulfide bonds, and polypeptides with N-terminal to C-terminal covalent bonds, such as short bacitracin S and short bacitracin tyrosine. Alpha-helical antibacterial peptides are more linear molecules that exist in disordered structures in aqueous media, but they interact with hydrophobic cell membranes to form amphiphilic helical structures, such as cecropin, magainin and melittin.

[0006] As a new type of antibiotic, antibacterial peptides are not prone to cause drug resistance in microorganisms and have broad application prospects. However, antibacterial peptides directly obtained from organisms have exclusivity to other organisms and are difficult to be directly applied to the human body, i.e. this type of antibacterial peptide has strong toxicity to the human body and cannot be directly used as a human drug. Therefore, there is a strong demand for artificially synthesized polypeptide drugs. SUMMARY

[0007] The present application aims to solve the problems of instability and easy hydrolysis of antibacterial peptides directly obtained from organisms in the body, and provides an antibacterial peptide and a pharmaceutical composition thereof and an application. By using artificial synthesis, the antibacterial peptide sequence is subjected to cyclization modification, which can improve the stability of the antibacterial peptide while maintaining good antibacterial activity, and is widely used in market production.

[0008] Indolicidine (Ile-Leu-Pro-Trp-Lys-Trp-Pro-Trp-Trp-Pro-Trp-Arg-Arg-NH2) is an antibacterial peptide isolated from the cytoplasmic granules of bovine neutrophilic granulocytes, which consists of 13 amino acids and is one of the smallest natural linear antibacterial peptides known so far. Indolicidin has a broad antibacterial spectrum and has strong antibacterial activity against a variety of aerobic gram-negative bacteria, gram-positive bacteria and fungi. The present patent is based on the polypeptide sequence of Indolicidine, in which the amino acids are replaced with amino acids of similar properties and a small number of functional amino acids that can be modified, and then the functional amino acids are connected by chemical means to form a cyclic peptide, obtaining a new antibacterial peptide which has the same level of antibacterial activity as Indolicidine, and the stability of the antibacterial peptide is improved by cyclization.

[0009] The technical scheme of the present application is as follows:

[0010] An antibacterial cyclic peptide, the amino acid sequence of which is shown as formula (I): H-Ile-Xaa2-Xaa3-Xaa4-Xaa5-Xaa6-Xaa7-Xaa8-Xaa9-Xaa 10 -Xaa 11 -Arg-Arg-NH2

[0011] Formula (I)

[0012] Wherein:

[0013] Xaa2 is selected from Leu, Cys, Hcy, Pen or S5 amino acid;

[0014] Xaa3 is selected from Pro, Cys, Hcy, Pen or S5 amino acid;

[0015] Xaa4 is selected from Trp, Cys, Hcy, Pen or S5 amino acid;

[0016] Xaa5 is selected from Lys, Cys, Hcy, Pen or S5 amino acid;

[0017] Xaa6 is selected from Trp, Cys, Hcy, Pen or S5 amino acid;

[0018] Xaa7 is selected from Pro, Cys, Hcy, Pen or S5 amino acid;

[0019] Xaa8 is selected from Trp, Cys, Hcy, Pen or S5 amino acid;

[0020] Xaa9 is selected from Trp, Cys, Hcy, Pen or S5 amino acid;

[0021] Xaa 10 is selected from Pro, Cys, Hcy, Pen or S5 amino acid;

[0022] Xaa 11 is selected from Trp, Cys, Hcy, Pen or S5 amino acid;

[0023] wherein,

[0024] only two amino acids are selected from Cys, Hcy, Pen or S5 amino acid;

[0025] and, when any one i-position amino acid among Xaa2 to Xaa7 is replaced by a Cys, Hcy, Pen or S5 amino acid, another i+4-position amino acid among Xaa6 to Xaa 11 is simultaneously replaced by the same Cys, Hcy, Pen or S5 amino acid, and the i and i+4-position amino acids are cross-linked to form a cyclic peptide, wherein i is 2-7, inclusive.

[0026] According to a preferred embodiment, Xaa4 and Xaa8 are simultaneously replaced by the same Cys, Hcy, Pen or S5 amino acid, and cross-linked at this position to form a cyclic peptide.

[0027] According to a preferred embodiment, Xaa7 and Xaa 11 are simultaneously replaced by the same Cys, Hcy, Pen or S5 amino acid, and cross-linked at this position to form a cyclic peptide.

[0028] According to a preferred embodiment, when the i and i+4-position amino acids are selected from one of Cys, Hcy or Pen, the i and i+4-position amino acids are connected by a cross-linking agent to form a cyclic peptide.

[0029] According to a preferred embodiment, the cross-linking agent is selected from one or more of m-dibromobenzyl, o-dibromobenzyl, p-dibromobenzyl or succinimide.

[0030] According to a preferred embodiment, when the i and i+4-position amino acids are S5 amino acids, the i and i+4-position amino acids are directly connected to form a cyclic peptide.

[0031] According to a preferred embodiment, the antibacterial cyclic peptide is as shown in SEQ ID No. 1 to SEQ ID No. 78. According to a preferred embodiment, the S5 amino acid is: a-Me-Gly(Pentenyl)-OH.

[0032] According to a preferred embodiment, the antibacterial cyclic peptide is N-terminally amidated, C-terminally acetylated, and all L-configuration amino acids are replaced by D-configuration amino acids.

[0033] The present application also provides a composition comprising an acceptable adjuvant and an antibacterial cyclic peptide as described above or a pharmaceutically acceptable salt, ester or solvate thereof.

[0034] The present application also provides the use of an antibacterial cyclic peptide as described above or a pharmaceutically acceptable salt, ester or solvate thereof and a pharmaceutical composition thereof in the preparation of a medicament for the control or prevention of microbial infection, the indications of which include wound infection, acne, diabetic foot ulcer, athlete's foot, onychomycosis, tinea, furuncle, impetigo, cellulitis, staphylococcal scalded skin syndrome, septic arthritis and bacteremia.

[0035] The present application also provides a method for preparing an antibacterial cyclic peptide as described above, comprising the following steps:

[0036] Step 1: using an amide resin, an Fmoc-protected amino acid, a coupling reagent and an organic base as starting materials, reacting in a protected organic solvent to obtain a Fmoc-protected amino acid-amide resin coupling product;

[0037] Step 2: using a solid phase method to sequentially couple amino acids with protecting groups to synthesize a side chain fully protected linear peptide;

[0038] Step 3: adding a cleavage agent to cleave the linear peptide from the resin, vacuum freeze-drying to obtain a crude polypeptide, and then purifying using preparative liquid chromatography;

[0039] Step 4: synthesizing a cyclic peptide crude product by reacting a linear peptide, a cross-linking agent and an organic base in a liquid phase, and directly purifying using preparative liquid chromatography.

[0040] According to a preferred embodiment, C4, C8 or C 18 A reverse phase chromatographic column is used to purify the peptide by AB linear elution using high performance liquid chromatography, with an elution rate of 1-20 mL / min; wherein the A mobile phase is an aqueous solution containing 0.01-0.5% TFA, and the B mobile phase is acetonitrile containing 0.01-0.5% TFA.

[0041] The present application also provides a pharmaceutical composition comprising an acceptable adjuvant and an antibacterial cyclic peptide as described above or a pharmaceutically acceptable salt, ester or solvate thereof. The above-mentioned composition can be a pharmaceutical composition or a health product composition. The adjuvant includes but is not limited to carriers, diluents, excipients or adjuvants well known to those skilled in the art.

[0042] The present application also provides the use of an antibacterial cyclic peptide as described above or a pharmaceutically acceptable salt, ester or solvate thereof and a pharmaceutical composition thereof in the preparation of a medicament for the control or prevention of microbial infection.

[0043] In an embodiment of the application, the synthesis of the antibacterial cyclic peptides as described herein, their stereoisomers, mixtures thereof, their pharmaceutically acceptable salts can be carried out according to any conventional method known in the state of the art, such as with the solid phase peptide synthesis method [Stewart J.M. y Young J.D., "Solid Phase Peptide Synthesis, 2nd edition", (1984), Pierce Chemical Company, Rockford, Illinois; Bodanzsky M. y Bodanzsky A., "The practice of Peptide Synthesis", (1994), Springer Verlag, Berlin; Lloyd Williams P. et al., "Chemical Approaches to the Synthesis of Peptides and Proteins", (1997), CRC, Boca Raton, FL, USA], synthesis in solution, enzymatic synthesis [Kullmann W. "Proteases as catalysts for enzymic syntheses of opioid peptides", (1980), J. Biol. Chem., 255(17), 8234-8238] or any combination thereof. The compounds can also be obtained by fermentation of genetically modified or unmodified bacterial strains with the aim of producing the desired sequence, or by controlled hydrolysis of proteins of animal, fungal or preferably plant origin, free containing peptide fragments of at least the desired sequence. For example, the compounds of the application can be produced using a nucleic acid sequence encoding the polypeptide amino acid sequence described herein, and optionally carrying out appropriate amino acid modifications.

[0044] By way of example only, the process for obtaining the polypeptide compounds of the application, their stereoisomers and mixtures thereof can comprise the following stages:

[0045] - coupling of an amino acid protected at the N-terminus and free at the C- terminus with an amino acid free at the N-terminus and protected or bound to a solid support at the C-terminus;

[0046] - eliminating the group protecting the N-terminus;

[0047] - repeating the coupling procedure and eliminating the group protecting the N- terminus until the desired peptide sequence is obtained;

[0048] - eliminating the group protecting the C-terminus or cleaving the solid support;

[0049] Preferably, the C-terminal is bound to a solid support and the process is carried out in solid phase, thus comprising the coupling of N-terminal protected and C-terminal free amino acids with N-terminal free and C-terminal bound to a polymeric support amino acids; elimination of the group protecting the N-terminal; and repeating the procedure as many times as necessary to obtain the desired length of the compound, which is finally followed by cleavage from the initial polymeric support.

[0050] Throughout the synthesis, the functional groups of the amino acid side chains are conveniently protected with temporary or permanent protecting groups and can be deprotected simultaneously or orthogonally to the process of cleaving the peptide from the polymeric support.

[0051] Alternatively, the solid phase synthesis can be carried out with a convergent strategy: coupling the peptide to the polymeric support or to a peptide or amino acid previously bound to the polymeric support. Convergent synthesis strategies are widely known to the person skilled in the art and are described in Lloyd-Williams P. et al., "Convergent Solid-Phase Peptide Synthesis", (1993), Tetrahedron, 49(48), 11065-11133.

[0052] The process of the present application can include additional stages of C-terminal deprotection and / or cleavage of the peptide from the polymeric support in any order without distinction, using standard procedures and conditions known in the state of the art; after which these terminal functional groups can be modified. The optional modification of the C-terminal can be carried out while the polypeptide compound of formula (I) is fixed to the polymeric support or once the polypeptide compound has been separated from the polymeric support.

[0053] The person skilled in the art will readily understand that the deprotection / cleavage steps of the C-terminal and N-terminal and their subsequent derivatization can be carried out in different order according to processes known in the state of the art.

[0054] The advantages of the present application compared to the existing technology are:

[0055] The antibacterial peptide provided by the present application is based on the structure of natural antibacterial peptide, in which similar nature amino acids and a small amount of modifiable functional amino acids are used to replace the amino acids, and then the functional amino acids are connected by chemical means to form a cyclic peptide, obtaining a new antibacterial peptide which has the same antibacterial activity as the original antibacterial peptide, and the stability of the antibacterial peptide is improved by cyclization. The antibacterial cyclic peptide of the present application maintains or improves the antibacterial activity of the natural antibacterial cyclic peptide, and improves the stability of the antibacterial peptide, which can be widely used for preparing antibacterial drugs and widely used. DETAILED DESCRIPTION

[0056] To further illustrate the present application, the polypeptide compounds provided by the present application and the use thereof are described in detail below in conjunction with examples.

[0057] Those skilled in the art will appreciate that the following examples are included to illustrate, and not to limit, the scope of the present application. Unless otherwise indicated, conventional conditions or manufacturer's recommended conditions are employed in the examples. Unless otherwise indicated, the reagents or instruments used in the examples are conventional products available on the market.

[0058] The features and properties of the present application are further described in detail below in conjunction with examples.

[0059] Examples 1-78: Preparation of compounds 1-78

[0060] The polypeptide synthesis adopts the standard Fmoc solid-phase method. The Rink Amide resin is selected, and the peptide chain is elongated from the C-terminal to the N-terminal.

[0061] The protected amino acids include: Fmoc-Ala-OH, Fmoc-Leu-OH, Fmoc-Ile-OH, Fmoc-Phe-OH, Fmoc-Pro-OH, Fmoc-Trp(Boc)-OH, Fmoc-Val-OH, Fmoc-Met-OH, Fmoc-Lys(Boc)-OH, Fmoc-Arg(Pbf)-OH, Fmoc-His(Boc)-OH, Fmoc-Cys(Trt)-OH, Fmoc-Hcy(Trt)-OH, Fmoc-Pen(Trt)-OH, Fmoc-α-Me-Gly(Pentenyl)-OH. The condensing agent is HBTU / HOBt / DIEA. The deprotection reagent is piperidine / DMF solution. The crude peptide is stored after being dissolved in water and freeze-dried. The purified peptide is separated and purified by medium pressure liquid chromatography or high performance liquid chromatography (HPLC), and the content of the pure peptide is greater than 85%. The molecular weight of the peptide sequence is determined by matrix-assisted laser desorption / ionization time-of-flight mass spectrometry (MALDI-TOF-MS). The linear peptide is cross-linked into a ring in the presence of an activated base, and the cross-linking agent includes m-dibromobenzyl, o-dibromobenzyl, p-dibromobenzyl or succinimide; the linear peptide containing Fmoc-α-Me-Gly(Pentenyl)-OH is separated and purified by medium pressure liquid chromatography or high performance liquid chromatography (HPLC) after the reaction solution is ringed, and the content of the pure peptide is greater than 90%.

[0062] Synthesis of the peptide sequence:

[0063] The synthesis conditions are as follows:

[0064] Protected amino acids (natural or unnatural): 2M DMF solution,

[0065] Condensing agent: 3M HBTU / HOBt in DMF,

[0066] Activating base: 2M DIEA in DMF,

[0067] Deprotection reagent: 20% v / v piperidine in DMF,

[0068] Crosslinker activating base solution: 6 eq of crosslinker (m-dibromobenzyl, o-dibromobenzyl, p-dibromobenzyl or dibromosuccinimide) in acetonitrile / water (1:1 by volume) with DIEA.

[0069] Step 1: Fmoc protected amino acid-amide resin coupling product was obtained by reacting amide resin, Fmoc protected amino acid, coupling reagent and organic base as starting materials in a protected organic solvent.

[0070] Step 2: Synthesized side chain fully protected linear peptide by coupling amino acids with protecting groups one by one using solid phase method.

[0071] Step 2.1: Deprotection: weigh Rink Amide resin 2.3 g (1 mmol) and place it in a polypeptide synthesis reactor, then prepare the deprotection reagent according to the above concentration and add it to the resin, react at room temperature, dry, add piperidine / DMF again, react at room temperature, dry, and wash with DMF until the test is qualified.

[0072] Step 2.2: Condensation reaction: under ice bath conditions, add amino acid and condensing agent to DMF activation, then add activating base to obtain activated solution, finally add the activated solution to the resin, react at room temperature, then use 5% ninhydrin color reagent to color the resin, the resin changes color, dry the solvent and wash with DMF, dry the solvent after the test is qualified, at this time the condensation reaction is complete.

[0073] Repeat the above deprotection and condensation reactions until the synthesis of the peptide chain is complete to obtain a peptide resin containing the complete polypeptide sequence structure.

[0074] Step 3: Add a cleavage agent to cleave the linear peptide from the resin, vacuum freeze-dry to obtain the crude polypeptide, and then purify it using preparative liquid chromatography.

[0075] Step 3.1: Cleavage of the peptide resin: Weigh 7 g of the synthesized peptide resin and put it into a 250 mL flask, ice bath, electromagnetic stirring. Prepare the cleavage solution

cleavage solution (volume percentage): trifluoroacetic acid: triisopropylsilane: ethanedithiol: water = 92.5:2.5:2.5:2.5

[0076] Step 3.2: Purification of linear crude peptide: The crude peptide is purified by medium pressure or high performance liquid chromatography. The chromatographic column is a C18 column, and the eluent is acetonitrile, water and a small amount of trifluoroacetic acid. The specific operation steps are as follows: weigh 1.00 g of crude peptide, add 20 mL of water and 5 mL of acetonitrile to dissolve the solid, centrifuge for 10 min (5000 rpm), and take the supernatant for sample loading. The chromatographic column is pre-equilibrated with 5% acetonitrile / water / 0.1% trifluoroacetic acid solution 200 mL. After sample loading, continue to flush with 5% acetonitrile / water / 0.1% trifluoroacetic acid solution 200 mL, and detect the composition of the eluent by high performance liquid chromatography. According to the liquid chromatography detection results, gradually increase the acetonitrile content until the purified polypeptide main peak is eluted. Combine the eluent, remove most of the solvent by rotary evaporation, and freeze-dry the pure polypeptide. The HPLC detection content is greater than 85%, and the molecular weight is confirmed by MALDI-TOF-MS.

[0077] Step 4: Subscription of linear peptide, cross-linking agent and organic base in liquid phase to obtain crude cyclic peptide, and direct use of preparative liquid chromatography for purification: Take 0.1 g of linear peptide, stir in 10 mL of activated base solution with cross-linking agent at room temperature for 240 min-24 h, after the reaction is completed, add 20 mL of double distilled water and sample. The chromatographic column is pre-equilibrated with 5% acetonitrile / water / 0.1% trifluoroacetic acid solution 200 mL. After sample loading, continue to flush with 5% acetonitrile / water / 0.1% trifluoroacetic acid solution 200 mL, and detect the composition of the eluent by high performance liquid chromatography. According to the liquid chromatography detection results, gradually increase the acetonitrile content until the purified polypeptide main peak is eluted. Combine the eluent, remove most of the solvent by rotary evaporation, and freeze-dry the pure polypeptide. The HPLC detection content is greater than 90%, and the molecular weight is confirmed by MALDI-TOF-MS.

[0078] The prepared antibacterial cyclic peptide compounds are shown in Table 1.

[0079] Table 1 List of synthesized antibacterial cyclic peptide compounds

[0080]

[0081]

[0082]

[0083]

[0084]

[0085]

[0086]

[0087]

[0088]

[0089]

[0090]

[0091]

[0092] Example 79: In vitro bacterial drug susceptibility test (MIC) of antibacterial cyclic peptides 50 )

[0093] The screening of antibacterial cyclic peptides is accomplished by in vitro bacterial drug susceptibility test. By determining the sensitivity or drug resistance level of bacteria to antibacterial cyclic peptides in vitro, the bacteriostatic effect of antibacterial cyclic peptides can be evaluated.

[0094] 1. Experimental process

[0095] 1.1 Test strains

[0096] The test strains are methicillin-resistant Staphylococcus aureus MRSA, methicillin-sensitive Staphylococcus aureus MSSA, and methicillin-resistant Staphylococcus epidermidis MRSE. The quality control strain is Staphylococcus aureus ATCC 29213. The test strains are cultured in MHA medium at 35-37°C for 24h.

[0097] Bacterial solution preparation: Each strain of bacteria is purified by agar plate before the test. After 35-37°C culture, a single colony is picked and adjusted to about 0.5 McFarland units (about 10 8 CFU / ml) by the McFarland turbidity method. The suspension is diluted 100-fold for agar double dilution method, and the diluted bacterial solution is inoculated on the prepared MH agar plate by a multipoint inoculator. The suspension is diluted 1000-fold for micro broth method.

[0098] 1.2 Test procedure

[0099] The concentration of the antibacterial cyclic peptide was set to be in the range of 0.008-128 μg / ml by double dilution. 1 ml of the antibacterial cyclic peptide solution was added into a sterile flat dish, and then 14 ml of melted MHA medium at 50°C was added and mixed. The final concentration of the antibacterial cyclic peptide in each dish was 128, 64, 32, 16, 8, 4, 2, 1, 0.5, 0.25, 0.125, 0.06, 0.03, 0.015, 0.008 μg / ml, respectively. After cooling, the bacteria were inoculated into the dish by a multipoint inoculator, and the dish was covered with a lid. The MHA medium was used, and the culture was carried out at 35-37°C for 24 h. After the culture, visual observation was carried out. The lowest sample concentration without bacterial growth in the dish was the minimum inhibitory concentration (MIC) of the antibacterial cyclic peptide. Meanwhile, a bacterial control without any sample and a blank medium control were set up.

[0100] According to the above method, the results of the in vitro bacterial drug sensitivity test are shown in Table 2.

[0101] Table 2 Minimum inhibitory concentration (MIC) of the antibacterial cyclic peptide against three kinds of bacteria 50 (μg / ml)

[0102]

[0103]

[0104]

[0105] From the results in Table 2, it can be seen that among the antibacterial cyclic peptides prepared in the present application, a plurality of antibacterial cyclic peptides showed in vitro antibacterial activity, and even the MIC of some antibacterial cyclic peptides reached 16, 8 or even 4. 50

[0106] The above-described embodiments only express the specific implementation of the present application, and the description is more specific and detailed, but it should not be understood as a limitation on the protection scope of the present application. It should be noted that for those skilled in the art, without departing from the technical concept of the present application, a number of modifications and improvements can be made, which are all within the protection scope of the present application.​

Claims

1. An antibacterial cyclic peptide, characterized in that, H-Ile-Xaa2-Xaa3-Xaa4-Xaa5-Xaa6-Xaa7-Xaa8-Xaa9-Xaa 10 -Arg-Arg-NH2 11 -Arg-Arg-NH2 Formula (I) wherein: Xaa2 is selected from Leu, Cys, Hcy, Pen or S5 amino acid; Xaa3 is selected from Pro, Cys, Hcy, Pen or S5 amino acid; Xaa4 is selected from Trp, Cys, Hcy, Pen or S5 amino acid; Xaa5 is selected from Lys, Cys, Hcy, Pen or S5 amino acid; Xaa6 is selected from Trp, Cys, Hcy, Pen or S5 amino acid; Xaa7 is selected from Pro, Cys, Hcy, Pen or S5 amino acid; Xaa8 is selected from Trp, Cys, Hcy, Pen or S5 amino acid; Xaa9 is selected from Trp, Cys, Hcy, Pen or S5 amino acid; Xaa 10 is selected from Pro, Cys, Hcy, Pen or S5 amino acids; Xaa 11 is selected from Trp, Cys, Hcy, Pen or S5 amino acids; wherein: only two amino acids are selected from Cys, Hcy, Pen or S5 amino acid; wherein the S5 amino acid is: a-Me-Gly(Pentenyl)-OH, And, when any one i-position amino acid among Xaa2to Xaa7is replaced by a Cys, Hcy, Pen or S5amino acid, Xaa6to Xaa 11 another i+4-position amino acid in the same peptide is simultaneously replaced by the same Cys, Hcy, Pen or S5amino acid, and the i and i+4-position amino acids are cross-linked to form a cyclic peptide, wherein i has a value of 2-7, inclusive.

2. The antibacterial cyclic peptide of claim 1, wherein Xaa4 and Xaa8 are simultaneously replaced by the same Cys, Hcy, Pen or S5 amino acid, and cross-link to form a cyclic peptide at these positions.

3. The antibacterial cyclic peptide of claim 1, wherein Xaa7and Xaa 11 are simultaneously replaced by the same Cys, Hcy, Pen or S5 amino acid and are cross-linked at this position to form a cyclic peptide.

4. The antibacterial cyclic peptide according to any one of claims 1 to 3, wherein When the amino acids at positions i and i+4 are selected from one of Cys, Hcy or Pen, the amino acids at positions i and i+4 are linked by a cross-linker to form a cyclic peptide.

5. The antibacterial cyclic peptide of claim 4, wherein The cross-linker is selected from one or more of m-dibromobenzyl, o-dibromobenzyl, p-dibromobenzyl or succinimide.

6. The antibacterial cyclic peptide according to any one of claims 1 to 3, wherein When the amino acids at positions i and i+4 are S5 amino acids, the amino acids at positions i and i+4 are directly linked to form a cyclic peptide.

7. The antimicrobial cyclic peptide of claim 1, wherein The antibacterial cyclic peptides are shown in the following table: 。 8. A process for the preparation of an antibacterial cyclic peptide as claimed in any one of claims 1 to 7, wherein, comprising the following steps: Step 1: reacting starting materials of an amide resin, Fmoc-protected amino acid, coupling reagent and organic base in a protected organic solvent to obtain a Fmoc-protected amino acid-amide resin coupling product; Step 2: synthesizing a side chain fully protected linear peptide by sequentially coupling amino acids with protecting groups using solid phase method; Step 3: adding a cleavage agent to cleave the linear peptide from the resin, vacuum freeze-drying to obtain a crude polypeptide, and then purifying using preparative liquid chromatography; Step 4: synthesizing a cyclic peptide crude product by reacting a linear peptide, a cross-linker and an organic base in liquid phase, and directly purifying using preparative liquid chromatography.

9. A composition characterized in that, comprising acceptable adjuvants and an antibacterial cyclic peptide or a pharmaceutically acceptable salt, ester or solvate thereof according to any one of claims 1-7.

10. Use of an antibacterial cyclic peptide or a pharmaceutically acceptable salt, ester, solvate thereof and a pharmaceutical composition thereof according to any one of claims 1-7 in the preparation of a medicament for the control or prevention of microbial infections, the indications of which are wound infections caused by Staphylococcus aureus infection, diabetic foot ulcers, furuncles, impetigo, cellulitis, staphylococcal scalded skin syndrome, septic arthritis and bacteremia or acne caused by epidermal Staphylococcus infection.

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