CN116515102B

CN116515102B - Star-shaped β-antibacterial glycopeptide, preparation method and application thereof

Info

Publication number: CN116515102B
Application number: CN202210076643.9A
Authority: CN
Inventors: 司张勇; 朱潇
Original assignee: Suzhou Wanwei Life Science Technology Co ltd
Current assignee: Suzhou Wanwei Life Science Technology Co ltd
Priority date: 2022-01-21
Filing date: 2022-01-21
Publication date: 2025-04-18
Anticipated expiration: 2042-01-21
Also published as: CN116515102A

Abstract

The application discloses a star-shaped beta-antibacterial glycopeptide, a preparation method and application thereof. The star-shaped beta-antibacterial glycopeptide has a structure shown in a general formula (I): the definition of each substituent group in the general formula (I) is the same as that in the specification. The star-shaped beta-antibacterial glycopeptide or the pharmaceutically acceptable salt thereof has good biocompatibility and antibacterial property and low cytotoxicity, and can be used in combination with different antibiotics, so that the sterilization effect of the antibiotics is recovered and enhanced.

Description

Star-shaped beta-antibacterial glycopeptide, and preparation method and application thereof

Technical Field

The application particularly relates to a star-shaped beta-antibacterial glycopeptide, a preparation method thereof and application thereof in medicine, and belongs to the field of medicine.

Background

The discovery and application of antibiotics has greatly driven the development of modern medicine. However, in antibiotic therapy over the last decades, bacteria have inevitably selected escape mutations to develop resistance to antibiotics. Carbapenem antibiotics are the last potent antibiotic of currently refractory gram-negative bacterial infections. However, the massive use of carbapenem drugs in hospitals has promoted the rapid emergence and spread of carbapenem-resistant gram-negative bacteria. Meanwhile, although various efforts have been made to develop novel antibiotics, the discovery of novel antibiotics has been almost in a state of stagnation, and no new type of antibiotics that can kill gram-negative bacteria have been discovered in the past fifty years.

Among the most significant challenges are gram-negative bacteria having a low-permeability outer membrane that impedes the passage of drug molecules to internal bacterial targets and a high-efficiency efflux pump system that can drain antibiotics to internal bacterial targets out of the bacterial body. These two processes greatly limit the concentration accumulation of antibiotics at their drug targets, resulting in antibiotic inefficiency. Gram-negative bacteria resistant to carbapenems have now been listed by the world health organization as a class of bacteria that is urgently needed to find new antibiotics or new treatments.

The discovery of natural antimicrobial peptides has greatly motivated extensive research into such antimicrobial agents in an effort to convert them into clinical use. Because of their rapid broad-spectrum antimicrobial efficacy and low frequency of drug resistance. Although the initial experimental results are exciting, more than three thousand antimicrobial peptides were found, natural antimicrobial peptides have limited success from research findings to conversion to clinical applications, and so far only five natural antimicrobial peptides have been approved for clinical applications, including nisin, gramicidin, polymyxin, daptomycin, and melittin. Among the various reasons, the main drawbacks are their cytotoxicity, instability in vivo, ease of adsorption by proteins and high production costs.

The beta polypeptide has one more methylene group in the backbone compared to the native alpha polypeptide. This gives the beta polypeptide greater flexibility in the molecular chain, allowing different types of secondary structures to be formed to exhibit an amphiphilic conformation, which is one of the key elements contributing to the antibacterial activity of the antibacterial peptide. Another prominent feature of beta polypeptides is their resistance to proteolytic cleavage, thereby improving in vivo stability. These properties make beta polypeptides attractive as candidate antibacterial agents. However, the antibacterial property, biocompatibility and the like of the existing beta polypeptides still need to be further improved.

Disclosure of Invention

The application mainly aims to provide a star-shaped beta-antibacterial glycopeptide, a preparation method thereof and application thereof in medicines, so as to overcome the defects of the prior art.

In order to achieve the purpose of the application, the technical scheme adopted by the application comprises the following steps:

In a first aspect the present application provides a compound of formula (I):

Wherein Core is a structural unit having a cyclic group;

R ₁、R₂、R₃、R₄ is each independently selected from H, halogen, substituted or unsubstituted C1-C20 alkyl, substituted or unsubstituted C1-C20 alkoxy, substituted or unsubstituted C2-C20 alkenyl, substituted or unsubstituted C2-C20 alkynyl, substituted or unsubstituted C3-C20 cycloaliphatic, substituted or unsubstituted C6-C15 aryl, substituted or unsubstituted C7-C30 alkyl-aryl, substituted or unsubstituted C3-C20 heterocycle, substituted or unsubstituted C4-C30 alkyl-heterocycle, substituted or unsubstituted C5-C15 heteroaryl, C1-C20 hydroxyalkyl, cyano, amino, guanidino, nitro or hydroxy;

n is 0 to 6, m is 3 to 100, x y is 1 to 50.

In a second aspect of the application, there is provided a star-shaped beta-antibacterial glycopeptide comprising an outer layer comprising a glycopeptide block of helical structure and an inner layer comprising a polydimethylamino beta-lactam block having a positive charge. The structure of the star-shaped beta-antibacterial glycopeptide is shown as a general formula (I).

In a third aspect, the present application provides a process for preparing a compound of formula (I), the process comprising:

(i) According to the reaction formula a, a precursor compound containing Core is polymerized with a compound shown in a formula (II) and a compound shown in a formula (III) to obtain a polymer shown in a formula (IV);

(ii) Deprotection of a Polymer of formula (IV) according to reaction formula b

In a fourth aspect, the present application provides a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

In a fifth aspect the present application provides the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as an antibacterial agent.

In a sixth aspect, the present application provides the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as described herein, in the manufacture of a medicament for the treatment or prophylaxis of a bacterial infection or a disease caused by such a bacterial infection.

In a seventh aspect, the present application provides the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition as an inhibitor of extracellular pumps and/or a bacterial membrane permeabilizing agent.

In an eighth aspect the present application provides a method of treating or preventing a bacterial infection or a disease caused by said bacterial infection in a subject, the method comprising administering to the subject an effective amount of a compound of formula (I) or said pharmaceutical composition.

In some embodiments, the bacteria are multi-drug resistant.

In some embodiments, the methods further comprise administering to the subject an effective amount of an additional antimicrobial agent. Such other antibacterial agents include, but are not limited to, ampicillin, cloxacillin, oxacillin and piperacillin, cephalosporins such as cefaclor, cefamandole, cefazolin, cefotaxime, cefoxitin, ceftazidime, ceftriaxone and cephalosporins, carbapenems including, for example, imipenem and meropenem, and glycopeptides, macrolides, quinolones, tetracyclines and aminoglycosides. In addition, the other antibacterial agent may be selected from rifampicin, ciprofloxacin, levofloxacin, piperacillin, compound neonomine, gentamicin, lobamycin, erythromycin, clarithromycin, novobiocin, spiramycin, acetylspiramycin, chloramphenicol, trimethoprim, sulfamethoxazole, carbenicillin, polymyxin B, colistin, amikacin, kanamycin, neomycin, netilmicin, streptomycin, tobramycin, paromomycin, geldanamycin, herbimycin, chlorocarbon cephalosporin, doripenem, cilastatin, cefadroxil, cefalotin, cefalexin, cefamandole, cefprozil, cefuroxime, cefixime, cefdinir, cefditoren, cefpodoxime, ceftibuten, ceftizoxime, cefepime, teicoplanin, vancomycin, ceftizoxime, cefradine, cefuroxime, ceftizoxime, ceftivalin, ceftizoxime, ceftivalis, and ceftivalin roxithromycin, dactylosin, telithromycin, spectinomycin, amoxicillin, carbenicillin, dicloxacillin, flucloxacillin, mezlocillin, methicillin, nafcillin, penicillin, ticarcillin, bacitracin, enoxacin, gatifloxacin, moxifloxacin, any one or a combination of more of norfloxacin, trovafloxacin, sulfamuron, azo sulfanilamide, sulfacetamide, sulfamethoxazole, sulfasalazine, sulfamethoxazole, trimethoprim, doxycycline, minocycline, oxytetracycline, tetracycline, flunomamine, clindamycin, lincomycin, ethambutol, fosfomycin, fusidic acid, furazolidone, isoniazid, linezolid, bisoxaden, mupirocin, nitrofurantoin, pyrazinamide, quinine/dalfopristin, ifosfamide, tinidazole.

The compound shown in the general formula (I) is a non-natural beta antibacterial glycopeptide, the chemical structure of the compound is represented as a block star polymer, the outer layer of the compound is a glycopeptide block with a spiral structure, the inner layer of the compound is a polydimethyl amino beta lactam block with positive charges, through the star structure, the compound can not only play the roles of increasing the permeability of a bacterial outer membrane and damaging the bacterial molecular efflux pump, but also simulate the cell surface polysaccharide molecules by utilizing the glycopeptide block of the outer layer to further inhibit bacterial infection, and simultaneously, the protein adsorption can be further reduced by forming a hydration isolation layer, and especially, the cytotoxicity caused by positive charges can be better reduced. The compound or its salt can be used in combination with different antibiotics to restore and enhance the bactericidal effect of the antibiotics.

Drawings

In order to more clearly illustrate the embodiments of the present application or the technical solutions in the prior art, the drawings that are required to be used in the embodiments or the description of the prior art will be briefly described below, and it is obvious that the drawings in the following description are only some embodiments described in the present application, and other drawings may be obtained according to the drawings without inventive effort to those skilled in the art.

FIG. 1 shows a 1H NMR spectrum of a star-shaped β -antibacterial glycopeptide of example 1.

FIG. 2 shows a gel permeation chromatogram of a star-type β -antimicrobial glycopeptide prior to deprotection in example 1.

FIG. 3 shows cytotoxicity of a star-shaped β -antibacterial glycopeptide prior to deprotection in example 1.

Figure 4 shows the bactericidal effect of star beta-antimicrobial glycopeptides on the carbapenem-resistant acinetobacter baumannii as demonstrated by the checkerboard broth microdilution assay in example 1.

Fig. 5 shows the bactericidal effect of star beta-antibacterial glycopeptides on carbapenem-resistant acinetobacter baumannii as demonstrated by the checkerboard broth microdilution assay in example 1.

FIG. 6 shows the bactericidal effect of the apparent star beta-antimicrobial glycopeptides on the carbapenem-resistant Acinetobacter baumannii in example 1 as measured by checkerboard broth microdilution.

FIG. 7 shows the bactericidal effect of erythromycin on the carbapenem-resistant Acinetobacter baumannii as demonstrated by the checkerboard broth microdilution assay in example 1.

FIG. 8 shows the bactericidal effect of star-shaped beta-antibacterial glycopeptides on the carbapenem-resistant Acinetobacter baumannii as demonstrated by the checkerboard broth microdilution assay in example 1.

Fig. 9 shows the bactericidal effect of star beta-antimicrobial glycopeptides on carbapenem-resistant acinetobacter baumannii as demonstrated by the checkerboard broth microdilution assay in example 1.

FIG. 10 shows the bactericidal effect of star-shaped beta-antibacterial glycopeptides on carbapenem-resistant Acinetobacter baumannii as demonstrated by the checkerboard broth microdilution assay in example 1.

Fig. 11 shows that the combination of star-shaped beta-antibacterial glycopeptide and rifampicin in example 1 has excellent bactericidal effect on the carbapenem-resistant acinetobacter baumannii as measured by a time sterilization curve.

Fig. 12 shows that the combination of star-shaped beta-antibacterial glycopeptides and novobiocin has excellent bactericidal effect on carbapenem-resistant acinetobacter baumannii as measured by a time sterilization curve in example 1.

Fig. 13 shows that the combination of star-shaped beta-antibacterial glycopeptides and clarithromycin has excellent bactericidal effect on the carbapenem-resistant acinetobacter baumannii as measured by a time sterilization curve in example 1.

FIG. 14 shows the bactericidal effect of star beta-antimicrobial glycopeptides on Acinetobacter baumannii (ATCC 19606) as demonstrated by the checkerboard broth microdilution assay in example 1.

FIG. 15 shows the bactericidal effect of erythromycin enhancement on Acinetobacter baumannii (ATCC 19606) by checkerboard broth microdilution assay in example 1, showing that the star-shaped β -antibacterial glycopeptides.

FIG. 16 shows the bactericidal effect of Star-shaped beta-antimicrobial glycopeptides on Acinetobacter baumannii (ATCC 19606) as demonstrated by a checkerboard broth microdilution assay in example 1.

Fig. 17 shows that the star beta-antibacterial glycopeptide enhances the bactericidal effect of roxithromycin against acinetobacter baumannii (ATCC 19606) as measured by checkerboard broth microdilution in example 1.

FIG. 18 shows the bactericidal effect of star beta-antimicrobial glycopeptides-enhanced acetylspiramycin on Acinetobacter baumannii (ATCC 19606) as demonstrated by a checkerboard broth microdilution assay in example 1.

FIG. 19 shows the bactericidal effect of erythromycin ethylsuccinate on Acinetobacter baumannii (ATCC 19606) as demonstrated by a checkerboard broth microdilution assay in example 1.

FIG. 20 shows the bactericidal effect of Star-shaped beta-antibacterial glycopeptides on Acinetobacter baumannii (ATCC 19606) as demonstrated by a checkerboard broth microdilution assay in example 1.

FIG. 21 shows the bactericidal effect of star beta-antimicrobial glycopeptides on A.baumannii (ATCC 19606) enhanced by the use of a checkerboard broth microdilution assay as described in example 1.

Detailed Description

In view of the shortcomings of the prior art, the inventor of the present application has long studied and put forward a great deal of practice, and the technical solution of the present application will be clearly and completely described below, and it is obvious that the described embodiments are some, but not all, embodiments of the present application. All other embodiments, which can be made by those skilled in the art based on the embodiments of the application without making any inventive effort, are intended to be within the scope of the application. It is further noted that, unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art.

Some embodiments of the present application provide a compound of formula (I):

or a stereoisomer, tautomer, N-oxide, hydrate, solvate, or salt of said compound, or a mixture of same, particularly a pharmaceutically acceptable salt of said compound;

Wherein Core is a structural unit having a cyclic group;

n is 0 to 6, m is 3 to 100, x y is 1 to 50.

In some embodiments, the structural units having a cyclic group include a substituted or unsubstituted 3-12 membered cycloalkyl group, a substituted or unsubstituted 3-12 membered heterocyclyl group, a substituted or unsubstituted 6-10 membered aryl group, or a substituted or unsubstituted 5-10 membered heteroaryl group, an organic macromolecular residue having a cyclic group (e.g., cyclodextrin molecular residue), or an inorganic compound molecular residue having a cyclic group (e.g., cage polysilsesquioxane molecular residue).

Further, the structural unit having a cyclic group is selected from a substituted or unsubstituted phenyl group.

In some more specific embodiments, the compound is a compound of formula (I-1):

Wherein R ₅、R₆ is selected from H, halogen, substituted or unsubstituted C1-C20 alkyl, substituted or unsubstituted C1-C20 alkoxy, substituted or unsubstituted C2-C20 alkenyl, substituted or unsubstituted C2-C20 alkynyl, substituted or unsubstituted C3-C20 cycloaliphatic, substituted or unsubstituted C6-C15 aryl, substituted or unsubstituted C7-C30 alkyl-aryl, substituted or unsubstituted C3-C20 heterocycle, substituted or unsubstituted C4-C30 alkyl-heterocycle, substituted or unsubstituted C5-C15 heteroaryl, C1-C20 hydroxyalkyl, cyano, amino, guanidino, nitro or hydroxy.

In some embodiments, the aforementioned alkyl groups may be linear or branched and may be optionally substituted, and may be selected from, for example, methyl, ethyl, 1-propyl or n-propyl, 2-propyl or isopropyl, 1-butyl or n-butyl, 2-methyl-1-propyl or isobutyl, 1-methylpropyl or sec-butyl, 1-dimethylethyl or tert-butyl, 1-pentyl, 2-pentyl, 3-pentyl, 2-methyl-2-butyl, 3-methyl-1-butyl, 2-methyl-1-butyl, 1-hexyl, 2-hexyl, 3-hexyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 3-methyl-3-pentyl, 2, 3-dimethyl-2-butyl, 3-dimethyl-2-butyl, and the like, without being limited thereto.

In some embodiments, the aforementioned alkoxy groups may be linear or branched, and may be selected from, for example, but not limited to, methoxy, ethoxy, propoxy, butoxy, and the like.

In some embodiments, the aforementioned alkenyl groups may be linear or branched, and may be optionally substituted, i.e., substituted or unsubstituted. For example, the aforementioned alkenyl groups may be selected from, but are not limited to, ethenyl, propenyl, butenyl, 1, 4-butadienyl, pentenyl, hexenyl, 4-methylhex-1-enyl, 4-ethyl-2-methylhex-1-enyl, and the like.

In some embodiments, the aforementioned alkynyl groups may be linear or branched, and may be optionally substituted. For example, the aforementioned alkynyl groups may be selected from, but are not limited to, ethynyl, propynyl, butynyl, and the like.

In some embodiments, the aforementioned cycloaliphatic includes cycloalkyl and cycloalkenyl groups, such as may be selected from, but not limited to, cyclopropane, cyclobutane, cyclopentane, cyclopentene, cyclopentadiene, cyclohexane, cyclohexene, 1, 3-cyclohexadiene, 1, 4-cyclohexadiene, cycloheptane, cycloheptene, and the like.

In some embodiments, the aryl group may be a 6-membered carbocyclic aromatic ring such as phenyl, or a 7-12-membered bicyclic ring such as naphthalene, indane, and 1,2,3, 4-tetrahydroquinoline, and the like, and is not limited thereto.

In some embodiments, the aforementioned heterocycle is an aliphatic spirocyclic ring comprising at least one heteroatom selected from N, O and S, which may be selected from, but is not limited to, 1-pyrrolidinyl, 2, 4-imidazolidinyl, 2, 3-pyrazolidinyl, 1-piperidinyl, 2-piperidinyl, 3-piperidinyl, 4-piperidinyl, 2, 5-piperazinyl, pyranyl, 2-morpholinyl, oxiranyl, aziridinyl, azetidinyl, tetrahydropyridinyl, thiomorpholinyl, thienyl, piperazinyl, homopiperazinyl, homopiperidinyl, azepanyl, oxacycloheptyl, thienyl, 1, 4-oxaheterocycloalkyl, 1, 4-dioxacycloheptane, 1, 4-oxacycloheptane, 1-oxacycloheptane, tetrahydrofuranyl, tetrahydrothienyl, 2-pyranyl, tetrahydrothienyl 3-pyrrolinyl, indolinyl, 2H-pyranyl, 4H-pyranyl, 1, 4-dioxanyl, 1, 3-dioxanyl, 1-dioxapyrrolidinyl, 3-dioxan, 1, 3-dioxa-pyrazolyl, 1, 3-dioxa-3, 1, 3-dioxa-pyrrolidinyl, and the like.

In some embodiments, the aforementioned alkylheterocycle refers to a chemical substituent comprising an alkyl group coupled to a heterocycle or substituted heterocycle.

In some embodiments, the foregoing heteroaryl refers to an aromatic heterocycle, which may be formed from five, six, seven, eight, nine or more atoms. Heteroaryl groups may be optionally substituted. For example, aromatic C5-C15 heterocyclic groups which may be selected from, but are not limited to, aromatic C5-C15 heterocyclic groups containing one oxygen or sulfur atom or up to four nitrogen atoms, or a combination of one oxygen or sulfur atom and up to two nitrogen atoms, and substitution thereof, as well as benzo-and pyrido-fused derivatives.

More preferably, R ₁、R₂、R₃ is each independently selected from C1-C6 alkyl, hydroxy, or amine.

In some cases, R ₃ may also be selected from amine groups, hydroxyl groups, and the like.

More preferably, R ₄、R₅、R₆ is a hydrogen atom.

In a more specific embodiment, the compound is a compound of the formula:

Some embodiments of the application also provide a star-shaped beta-antibacterial glycopeptide, wherein the outer layer is a glycopeptide block with a spiral structure, and the inner layer is a polydimethyl amino beta-lactam block with positive charges. The structure of the star-shaped beta-antibacterial glycopeptide is shown as a general formula (I).

Wherein the source of the glycopeptide block includes, but is not limited to, the monosaccharides glucose, galactose, mannose, altrose, aminoglucose, aminogalactose, aminomannose or disaccharide maltose.

The star-shaped beta-antibacterial glycopeptide provided by the embodiment of the application is a star-shaped block polymer, and the external spiral glycopeptide can be better exposed on the external layer of the compound to bind with a bacterial surface sugar receptor to prevent infection, form a hydration layer to prevent protein adsorption, block the combination of a cation block of the internal layer and mammalian cells, and further improve biocompatibility.

Some embodiments of the present application also provide a method for preparing a compound of formula (I), the method comprising:

(ii) Deprotection of a Polymer of formula (IV) according to reaction formula b

Wherein the compound having a protecting group represented by the formula (II) and the compound having a protecting group represented by the formula (III) can be synthesized in a manner known in the art. Glucose-derived beta lactams (AS (Bn)) can be synthesized, for example, according to literature (j.am.chem.soc.134, 16255-16264 (2012)). And, carboxybenzyl (Cbz) -protected amine-group-bearing beta lactam (DM (Cbz)) can be synthesized according to literature (angel.chem.int.ed.2020doi.org/10.1002/anie.201914304).

Wherein the definition of "protecting group" is known in the art and generally refers to a chemical group that reacts with and binds to a functional group in a molecule to prevent the functional group from participating in a subsequent reaction of the molecule, but which may then be removed to regenerate the unprotected functional group. In the present application, the protecting group includes, but is not limited to, benzyl, carboxybenzyl (Cbz), t-butoxycarbonyl (Boc), etc., preferably carboxybenzyl.

Further, step (a) comprises preparing the protective polymer in the presence of lithium bis (trimethylsilyl) amide and 4-t-butylbenzoyl chloride.

Further, the reaction temperature used in step (a) may be 0 ℃ to 66 ℃, preferably room temperature.

Further, step (b) comprises deprotecting the protected polymer under sodium and liquid ammonia conditions.

Further, the reaction temperature used in step (b) may be-80 to-50 ℃, preferably-78 to-55 ℃.

Some embodiments of the present application also provide a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

In the present specification, the definition of pharmaceutically acceptable salts is well known in the art, i.e., those salts which are suitable for use in contact with human tissue organs and tissue organs of lower animals without undue toxicity, irritation, allergic response, or the like, commensurate with a reasonable medicinal evaluation. The salt may be any salt, organic or inorganic addition salt, particularly any pharmaceutically acceptable organic or inorganic addition salt commonly used in pharmacy, for example a salt formed by the reaction of a compound of formula (I) with an inorganic acid such as hydrochloric acid, hydrobromic acid, hydroiodic acid or with an organic acid such as formic acid, acetic acid, acetoacetic acid, trifluoroacetic acid, trifluoromethanesulfonic acid, p-toluenesulfonic acid, methanesulfonic acid.

In some preferred embodiments, the pharmaceutical composition further comprises an additional antibacterial agent.

Further, such other antibacterial agents include, but are not limited to, ampicillin, cloxacillin, oxacillin and piperacillin, cephalosporins such as cefaclor, cefamandole, cefazolin, cefoperazone, cefotaxime, cefoxitin, ceftazidime, ceftriaxone and cephalosporins, carbapenems including, for example, imipenem and meropenem, and glycopeptides, macrolides, quinolones, tetracyclines and aminoglycosides. In addition, the other antibacterial agent may be selected from rifampicin, ciprofloxacin, levofloxacin, piperacillin, compound neonomine, gentamicin, lobamycin, erythromycin, clarithromycin, novobiocin, spiramycin, acetylspiramycin, chloramphenicol, trimethoprim, sulfamethoxazole, carbenicillin, polymyxin B, colistin, amikacin, kanamycin, neomycin, netilmicin, streptomycin, tobramycin, paromomycin, geldanamycin, herbimycin, chlorocarbon cephalosporin, doripenem, cilastatin, cefadroxil, cefalotin, cefalexin, cefamandole, cefprozil, cefuroxime, cefixime, cefdinir, cefditoren, cefpodoxime, ceftibuten, ceftizoxime, cefepime, teicoplanin, vancomycin, ceftizoxime, cefradine, cefuroxime, ceftizoxime, ceftivalin, ceftizoxime, ceftivalis, and ceftivalin roxithromycin, dactylosin, telithromycin, spectinomycin, amoxicillin, carbenicillin, dicloxacillin, flucloxacillin, mezlocillin, methicillin, nafcillin, penicillin, ticarcillin, bacitracin, enoxacin, gatifloxacin, moxifloxacin, any one or a combination of more of norfloxacin, trovafloxacin, sulfamuron, azo sulfanilamide, sulfacetamide, sulfamethoxazole, sulfasalazine, sulfamethoxazole, trimethoprim, doxycycline, minocycline, oxytetracycline, tetracycline, flunomamine, clindamycin, lincomycin, ethambutol, fosfomycin, fusidic acid, furazolidone, isoniazid, linezolid, bisoxaden, mupirocin, nitrofurantoin, pyrazinamide, quinine/dalfopristin, ifosfamide, tinidazole.

Wherein the other antimicrobial agent includes, but is not limited to, an anti-gram positive antibiotic, and the antimicrobial range of the antimicrobial agent includes gram negative bacteria. Further, the antibacterial range against gram-positive bacteria antibiotics can be extended by using the compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof, so that it is also effective against gram-negative bacteria.

In this specification, the aforementioned pharmaceutically acceptable carriers include pharmaceutically acceptable materials, compositions, excipients and the like, such as liquid or solid fillers, diluents, excipients or solvent encapsulating materials, including in particular but not limited to sugars such as lactose, dextrose and sucrose, starches such as corn starch and potato starch, celluloses and derivatives thereof such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate, tragacanth powder, malt, gelatin, talc, excipients such as cocoa butter and suppository waxes, oils such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil, glycols such as propylene glycol, polyols such as glycerol, sorbitol, mannitol and polyethylene glycol, ethyl oleate, ethyl laurate and the like, esters of agar, buffers such as magnesium hydroxide and aluminum hydroxide, alginic acid, sterile distilled water, ethanol, pH buffered solutions, polyesters, polycarbonates or polyanhydrides and the like.

In some embodiments, pharmaceutically inert inorganic or organic excipients may be used in order to prepare the pharmaceutical composition. For example, lactose, talc, stearic acid and its salts, fats, waxes, solid or liquid polyols, natural oils and hardened oils and the like can be used as pharmaceutically acceptable carriers for the preparation of pills, powders, gelatine capsules or suppositories and the like. For the preparation of injections, oral liquids, sprays, aerosol preparations, powders and the like, water, alcohols, glycerin, polyols and suitable mixtures thereof, vegetable oil and the like can be used as pharmaceutically acceptable carriers. Further, after the foregoing formulations are prepared, the formulations may be sterilized by a variety of means, including filtration through a bacteria-retaining filter, or by adding a sterilizing agent in the form of a sterile solid composition.

Some embodiments of the present application also provide the use of the compound of formula (I) or a pharmaceutically acceptable salt thereof or the pharmaceutical composition as an antibacterial agent.

In the present specification, the term "antibacterial agent" refers to any substance or combination thereof capable of (i) inhibiting, reducing or preventing the growth of bacteria, (ii) having the ability to inhibit or reduce the production of infection by bacteria in a subject, and (iii) having the ability to inhibit or reduce the proliferation of bacteria in the environment or to maintain infectivity.

Some embodiments of the present application also provide the use of a compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof or the pharmaceutical composition for the preparation of a medicament for treating or preventing a bacterial infection or a disease caused by the bacterial infection.

Wherein the bacteria include at least one of multi-drug resistant bacteria and sensitive bacteria.

Further, the bacteria are multi-resistant, i.e., the bacteria are resistant to multiple drugs of different chemical structures and/or resistant to drugs directed against different targets.

In the present specification, the bacteria include gram-negative bacteria (e.g., escherichia coli, pseudomonas aeruginosa, helicobacter pylori, klebsiella pneumoniae, etc.), gram-positive bacteria, etc., particularly carbapenem-resistant gram-negative bacteria such as carbapenem-resistant Acinetobacter baumannii.

In the present specification, the medicine may be in various forms of preparation, and may be used in various modes such as oral administration, injection, external application, embolism, aerosol, etc. Formulations suitable for oral administration may be in the form of tablets, troches, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, or syrups or elixirs and the like. The medicine may also contain sweetener, corrective, colorant, preservative and antioxidant. Formulations suitable for injection may be in the form of sterile injectable aqueous solutions or oleaginous suspensions, in which case solvents may be employed including, but not limited to, water, ringer's solution, sodium chloride solution, dextrose solution, and the like. The form of preparation suitable as a suppository is solid at ordinary temperature but liquid in the rectum, in which the drug carrier can dissolve to release the drug without irritating the rectum.

Some embodiments of the present application also provide the use of the compound of formula (I) or a pharmaceutically acceptable salt thereof or the pharmaceutical composition as an extracellular pump inhibitor and/or a bacterial membrane permeabilizing agent.

Wherein the definition of the extracellular pump inhibitor and/or bacterial membrane permeabilizing agent is well known in the art. Specifically, the extracellular matrix pump refers to a protein assembly that outputs substrate molecules from the cytoplasm or periplasm of a cell in an energy-dependent manner. By bacterial membrane permeabilizing agent is meant any compound that is capable of reducing the integrity of or disrupting the bacterial cytoplasmic membrane.

Some embodiments of the application also provide a method of treating or preventing a bacterial infection or a disease caused by the bacterial infection in a subject, the method comprising administering to the subject an effective amount of a compound of formula (I) or the pharmaceutical composition.

In some embodiments, the bacteria are multi-drug resistant.

In some embodiments, the methods further comprise administering to the subject an effective amount of an additional antimicrobial agent. The other antibacterial agents are as described above and will not be described in detail herein. And, the optimum dosage ratio of the compound of formula (I) to the other antibacterial agent can be determined by one skilled in the art in a manner known in the art.

The compounds of formula (I) may be administered to a subject in need thereof in an effective amount, alone or in combination (simultaneously, sequentially or separately) with one or more other antibacterial agents.

In this specification, the subject may be any human or non-human animal, preferably a mammal, more preferably a human.

Because of the synergistic effect of the compound of formula (I) in combination with the other antibacterial agent, the therapeutically effective dose of the compound of formula (I) and/or the other antibacterial agent alone may be lower than its standard dose. For example, the therapeutically effective dose can be a standard dose 1％～99％、1％～90％、1％～80％、1％～70％、1％～60％、1％～50％、1％～40％、1％～30％、1％～20％、5％～20％、1％～10％、0.1％～1％、0.01％～1％、0.001％～1％ or the like.

The technical scheme of the present application is further described in detail below with reference to several preferred embodiments and the accompanying drawings, and the embodiments are implemented on the premise of the technical scheme of the present application, and detailed implementation manners and specific operation processes are given, but the protection scope of the present application is not limited to the following embodiments.

Example 1 the structural formula of a star-shaped beta-antibacterial glycopeptide provided in this example is as follows:

the method for synthesizing the star-shaped beta-antibacterial glycopeptide comprises the following steps:

(1) Preparation of beta lactam monomer

Glucose-derived beta lactams (AS (Bn)) were synthesized according to literature (j.am.chem.soc.134, 16255-16264 (2012)). Carboxyl benzyl (Cbz) -protected amino-bearing beta lactam (DM (Cbz)) was synthesized according to the literature (Angew.chem.int.Ed.2020doi.org/10.1002/anie.201914304).

(2) General procedure for aggregation

The entire polymerization process is carried out in an inert gas-protected glove box. First, 0.4M DM (Cbz) and AS (Bn), 0.02M 1,3, 5-benzenetricarboxylic acid chloride and 0.15M lithium bis (trimethylsilyl) amide (LiHMDS) were prepared in anhydrous tetrahydrofuran. Then 1ml of 1,3, 5-benzenetricarboxylic acid chloride, 900. Mu.l of DM (Cbz) solution were added to a 10ml oven-dried round bottom flask and mixed. The solution was stirred at 30 ℃ for 3min to mix well. Subsequently 1ml of LiHMDS solution was injected into the reaction flask to initiate polymerization. After a period of reaction at room temperature, after confirming complete consumption of DM (Cbz) monomer by TLC, 450. Mu.l of AS (Bn) solution was added to the reaction mixture to continue the reaction until the monomer was completely consumed, after which the reaction was quenched with a few drops of methanol. The polymer was purified by repeated dissolution in dichloromethane (3 cycles) and precipitation in hexane.

(3) Polymer deprotection

140Mg of the protective polymer and 54mg of potassium tert-butoxide (KOT-Bu) were dissolved in 5.0ml of anhydrous THF. The polymer solution was added dropwise to a rapidly stirred solution of sodium (120 mg) in liquid ammonia (15 ml) at-78 ℃ and nitrogen. Washed in anhydrous toluene and hexane and cut into small pieces prior to addition. The reaction was allowed to react at-78 ℃ for 4h, then saturated ammonium chloride was added dropwise to quench the reaction until the blue color disappeared. The remaining ammonia was evaporated at room temperature overnight. The solution obtained by filtration is washed with deionized water and dialyzed with a 1000Da cut-off dialysis bag for 2 days, and water is changed every 2 to 3 hours. Finally, a white solid sample was obtained by freeze-drying.

The star-shaped beta-antibacterial glycopeptide is successfully synthesized by anion ring-opening polymerization, and is a block star-shaped beta-polypeptide. The outer layer of the block star-shaped beta-polypeptide is a glycopeptide block with a spiral structure, so that the effects of improving biocompatibility, preventing protein adsorption and preventing infection can be achieved, and the inner layer is a polydimethyl amino beta-lactam block with positive charges, so that the effects of increasing the permeability of a bacterial outer membrane and damaging a bacterial molecular efflux pump can be achieved. Referring to FIG. 1, the molecular structure of the polypeptide is proved by nuclear magnetic resonance hydrogen spectrum, the integral ratio of the outer glycopeptide block to the inner polydimethyl amino beta lactam block with positive charges is 1:2, and the integral ratio is consistent with the monomer feeding ratio. Referring to FIG. 2, the polymer having a molecular weight of the polypeptide as measured by Gel Permeation Chromatography (GPC) has a degree of polymerization of 26, a monomer/initiator feed ratio of approximately 27:1, and a relatively narrow molecular weight distribution。

Acinetobacter baumannii resistant to carbapenems is the first bacterium on the list of "superbacteria" most resistant to drugs and most threatening to human health in the world published by the World Health Organization (WHO). Table 1 shows the resistance to Acinetobacter carbapenem (DR-AB), which is almost always seen to be resistant to the antibiotics currently in clinical use.

In this example, the activity of the star-shaped beta-antibacterial glycopeptide was tested by using the bacterium, and the test method comprises:

1. Minimum Inhibitory Concentration (MIC) value detection

1) Activation A single colony was streaked from LB plates and added to a centrifuge tube containing 5ml of MHB medium, which was placed on a shaker at 37℃at 175rpm and shake-cultured overnight.

2) The re-cultivation is carried out by sucking 50. Mu.l of the activated bacteria liquid into a centrifuge tube containing 5ml of MHB culture medium and shaking cultivation for 3-4 hours.

3) An antibiotic solution (10 mg/ml) was prepared.

4) 50. Mu.L of MHB was added to each well of row B-F of a 96-well plate, and 50. Mu.L of MHB was aspirated to wells B1, C1, D1, E1, and F1, respectively.

5) 10.24. Mu.L of MHB was pipetted from wells B1, C1, D1, E1, F1, respectively, and discarded.

6) 10.24. Mu.L of antibiotic solution was pipetted into the B1, C1, D1, E1, F1 wells, respectively, and mixed well.

7) 50. Mu.L of the mixture was sucked from the first row (B2-F1) of wells to the second row (B2-F2) of wells and was blown and mixed well. And repeating the steps until the last row of hole sites (B12-F12).

8) Mu.L of the mixture was aspirated from the last row of wells (B12-F12) and discarded.

9) The bacteria were removed from the shaker.

10 Diluted bacterial suspension and the OD value was determined using an enzyme-labeled instrument until the bacterial suspension was diluted to OD ≡0.2 (at which point the bacterial solution was about 10 ⁹ CFU/ml). Then the bacterial suspension is diluted by 1000 times, thus obtaining 10 ⁶ CFU/ml bacterial suspension.

11 50. Mu.L, 106CFU/ml of bacterial suspension were aspirated into the top 5 rows of wells (B2-F12), respectively.

12 Aspiration of bacterial suspension and MHB positive and negative controls at the 6 th drain site (G2-G12) were filled (6 positive controls such as G2-G6: 100. Mu.L MHB;6 negative controls such as G7-G12: 50. Mu.L MHB+50. Mu.L bacterial suspension).

13 Shaking the 96-well plate to be tested for 3-4min, sealing, and then placing the 96-well plate into a biochemical incubator for culturing for 16-18 h at 37 ℃.

14 Taking out the 96-well plate from the incubator, visually observing turbidity to determine MIC value, measuring 595nm OD value by using an enzyme label instrument, recording, deriving data and judging according to the break point interpretation.

2. Chessboard dilution method for measuring combined medication effect

1) Activating, re-culturing the strain and preparing an antibiotic solution (the same as MIC experiment steps 1) -3).

2) A deep-well plate was used to laterally configure a 2-fold gradient concentration solution of the antibiotic (starting from 16 XMIC, the last well being MHB).

3) A deep-well plate was used to longitudinally configure a 2-fold gradient of the sample in concentration (starting from 4X 256. Mu.g/ml, the last well being MHB).

4) A multi-channel pipette is used for respectively sucking 25 mu L of antibiotic gradient concentration solution and sample gradient concentration solution from the deep hole plate, and the whole 96-well plate is filled up according to rows and columns.

5) 50. Mu.L of 106CFU/ml of bacterial suspension (configuration method identical to MIC test step 10) was added to each well.

6) Sealing, shaking, incubation and reading (same as MIC experimental steps 13) -14).

Through the above activity tests, it was found that the effects that can be achieved by using the star-shaped β -antibacterial glycopeptides of the present embodiment in combination with various antibiotic adjuvants include, but are not limited to:

(1) Increasing the antimicrobial range of antibiotics, antibiotics that are effective against gram-positive bacteria only (e.g., rifampicin) can also be made effective against gram-negative bacteria, see fig. 3;

(2) Greatly enhancing the sterilization effect of antibiotics and reducing the minimum sterilization concentration of various antibiotics by 16-256 times, see fig. 4-9;

(3) The possibility of bacterial drug resistance is reduced, because two molecules act on different positions simultaneously, and the bacteria can hardly make targeted mutation simultaneously.

Some experimental results of enhancing the bactericidal effect of other antibiotics on carbapenem-resistant acinetobacter baumannii by star-shaped beta-antibacterial glycopeptides in example 1 can be seen in fig. 4-13, and the bactericidal effect on common acinetobacter baumannii can be seen in fig. 14-21.

Example 2A star-shaped beta-antibacterial glycopeptide provided in this example has the following structural formula:

Wherein the Core structure is the same as Core in the star-shaped beta-antibacterial glycopeptide of example 1. Compared with example 1, the 1H NMR characterization map of the star-shaped beta-antibacterial glycopeptide comprises delta 5.66 (1H, br), 4.02-4.39 (3H), 3.65 (2H, br), 3.37-2.96 (9H), 1.37 (6H, br). The synthesis method of the star-shaped beta-antibacterial glycopeptide can be referred to in the example 1, but the adopted beta lactam monomer is monomethyl substituted beta lactam, the synthesis method is referred to in (J.Am.chem.Soc.2007, 129, 15474-15476), and other steps and raw materials are basically the same as those in the example 1.

Example 3A star-shaped beta-antibacterial glycopeptide provided in this example has the following structural formula:

Wherein the Core structure is the same as Core in the star-shaped beta-antibacterial glycopeptide of example 1. Compared with example 1, the 1HNMR characterization map of the star-shaped beta-antibacterial glycopeptide comprises delta 5.66 (1H, br), 4.02 (2H) and 3.65-2.75 (13H). The synthesis method of the star-shaped beta-antibacterial glycopeptide can be referred to in the example 1, but the adopted beta lactam monomer is beta lactam without methyl substitution, the synthesis method is referred to in (J.Am.chem.Soc.2014, 136, 4333-4342), and other steps and raw materials are basically the same as those in the example 1.

Example 4A star-shaped beta-antibacterial glycopeptide provided in this example has the following structural formula:

Wherein the Core structure is the same as Core in the star-shaped beta-antibacterial glycopeptide of example 1. Compared with example 1, the 1HNMR characterization map of the star-shaped beta-antibacterial glycopeptide comprises delta 5.66 (1H, br), 4.53 (2H, br) 4.02 (1H, br), 3.65 (2H, br), 3.37-2.58 (8H). The synthesis method of the star-shaped beta-antibacterial glycopeptide can refer to the example 1, but the adopted beta lactam monomer is single base-free substitution, and meanwhile, the methylene amino group protected by Cbz is changed from alpha position to beta position, the synthesis method is referred to (J.Am.chem.Soc.2013, 135, 5270-5273), and other steps and raw materials are basically the same as those of the example 1.

Example 5A structural formula of the star-shaped beta-antibacterial glycopeptide provided in this example is as follows:

Wherein the Core structure is the same as Core in the star-shaped beta-antibacterial glycopeptide of example 1. Compared with example 1, the 1H NMR characterization map of the star-shaped beta-antibacterial glycopeptide comprises delta 5.66 (1H, br), 4.32 (3H), 4.02 (2H), 3.65 (2H, br), 3.37-3.0 (5H), 2.50 (4H, br) and 1.8-1.3 (12H). The synthesis method of the star-shaped beta-antibacterial glycopeptide can refer to the example 1, but the adopted beta-lactam monomer is beta-lactam with no methyl substitution and an increase of 4 in the length of a Cbz protected methylene amino carbon chain, the synthesis method is referred to (Nat. Commun.2019,10, 1-14), and other steps and raw materials are basically the same as those of the example 1.

Example 6A star-shaped beta-antibacterial glycopeptide provided in this example has the following structural formula:

Wherein the Core structure is the same as Core in the star-shaped beta-antibacterial glycopeptide of example 1. Compared with example 1, the 1H NMR characterization map of the star-shaped beta-antibacterial glycopeptide comprises delta 5.66 (1H, br), 4.60-4.14 (1H), 4.12-3.52 (4H, br, m), 3.20-2.58 (7H, br, m), and 1.37 (12H, br, m). The synthesis method of the star-shaped beta-antibacterial glycopeptide can be referred to in example 1, but the adopted beta lactam monomer is changed from glucose to altrose lactam monomer, the synthesis method is referred to (J.Am.chem.Soc.2017, 139, 14217-14223), and other steps and raw materials are basically the same as those in example 1.

Example 7 the structural formula of the star-shaped beta-antibacterial glycopeptide provided in this example is as follows:

Wherein the Core structure is the same as Core in the star-shaped beta-antibacterial glycopeptide of example 1. Compared with example 1, the 1H NMR characterization map of the star-shaped beta-antibacterial glycopeptide comprises delta 5.82 (1H, br), 4.37-4.14 (1H), 4.12-3.52 (4H, br, m), 3.85-2.58 (11H, br, m), 1.37 (12H, br, m). The synthesis of this star-shaped beta-antibacterial glycopeptide can be described in example 1, but the beta lactam monomer used therein is changed from glucose to galactose lactam monomer, and the synthesis is described in (J.Am. Chem. Soc.2016,138, 6532-6540), and the other steps and raw materials are substantially the same as in example 1.

Example 8A structural formula of the star-shaped beta-antibacterial glycopeptide provided in this example is as follows:

Wherein Core is a1, 2,3, 4-cyclobutane tetracarbon group. Compared with example 1, the 1H NMR characterization map of the star-shaped beta-antibacterial glycopeptide comprises delta 5.66 (1H, br), 4.04 (1H), 3.77-3.53 (2H, br), 3.48-2.69 (9H, br, m) and 3.20-2.58,1.37 (12H, br). The synthesis method of the star-shaped beta-antibacterial glycopeptide can refer to the example 1, wherein in the step (2), 1,2,3, 4-cyclobutane tetraacyl chloride is adopted to replace 1,3, 5-benzene tricarboxylic acid chloride, and other steps and raw materials are basically the same as those in the example 1.

Example 9A star-shaped beta-antibacterial glycopeptide provided in this example has the following structural formula:

wherein Core is 1,2,3,4,5, 6-cyclohexane hexacarbon group. Compared with example 1, the 1H NMR characterization map of the star-shaped beta-antibacterial glycopeptide comprises delta 5.66 (1H, br), 4.04 (1H), 3.77-3.53 (2H, br), 3.48-2.69 (9H, br, m) and 3.20-2.58,1.37 (12H, br). The synthesis method of the star-shaped beta-antibacterial glycopeptide can refer to the embodiment 1, wherein 1,2,3,4,5, 6-cyclohexane hexaacyl chloride is adopted to replace 1,3, 5-benzene trimethyl acyl chloride in the step (2), and other steps and raw materials are basically the same as the embodiment 1.

Referring to the method of example 1, the activity of the star-shaped beta-antibacterial glycopeptides provided in examples 2 to 9 was tested by using the carbapenem-resistant acinetobacter baumannii in this example, and the results show that the star-shaped beta-antibacterial glycopeptides can also increase the sterilization range of antibiotics, enhance the sterilization effect of antibiotics, reduce the possibility of bacterial resistance, and have an effect similar to that of the antibacterial glycopeptides of example 1 when used in combination with various antibiotic adjuvants.

In addition, the present inventors have prepared other star-shaped β -antibacterial glycopeptides described in the present specification with reference to the foregoing examples 1 to 9 and have also tested their antibacterial properties and the like, and have shown that these star-shaped β -antibacterial glycopeptides are used in combination with various antibiotic adjuvants, and have far superior effects in increasing the antibacterial range of antibiotics, enhancing the antibacterial effect of antibiotics, reducing the possibility of bacterial resistance generation and the like to those of conventional glycogenic cationic block poly (β -peptide), β -peptide glycocopolymers and the like.

It should be understood that the technical solution of the present application is not limited to the above specific embodiments, and all technical modifications made according to the technical solution of the present application without departing from the spirit of the present application and the scope of the claims are within the scope of the present application.

TABLE 1 resistance to carbapenem Acinetobacter baumannii (CR-AB)

Antibiotics	MIC(μg/ml)	Drug resistance
			Ciprofloxacin	>=4	Drug resistance
Ampicillin/sulbactam	>=32	Drug resistance
			Levofloxacin	>=8	Drug resistance
Piperacillin	>=128	Drug resistance
			Compound Xinnoming	>=320	Drug resistance
Gentamicin	>=16	Drug resistance
			Cefoperazone/sulbactam	8	Drug resistance
Ceftazidime	>=64	Drug resistance
			Ceftriaxone	>=64	Drug resistance
Cefepime	>=64	Drug resistance
			Piperacillin/tazobactam	>=128	Drug resistance
Meropenem	>=16	Drug resistance
			Lobamycin	>=16	Drug resistance
Imipenem	>=16	Drug resistance

Claims

1. A compound represented by general formula (I):

Formula (I)

Wherein, Core is a structural unit having a cyclic group;

R ₁ , R ₂ , R ₃ , and R ₄ are each independently selected from H, halogen, substituted or unsubstituted C1-C20 alkyl, substituted or unsubstituted C1-C20 alkoxy, substituted or unsubstituted C2-C20 alkenyl, substituted or unsubstituted C2-C20 alkynyl, substituted or unsubstituted C3-C20 alicyclic, substituted or unsubstituted C6-C15 aryl, substituted or unsubstituted C7-C30 alkyl-aryl, substituted or unsubstituted C3-C20 heterocycle, substituted or unsubstituted C4-C30 alkyl-heterocycle, substituted or unsubstituted C5-C15 heteroaryl, C1-C20 hydroxyalkyl, cyano, amino, guanidino, nitro, or hydroxyl;

n is 0~6, m is 3~100, x and y are 1~50.

2. The compound of general formula (I) according to claim 1, characterized in that: the structural unit having a cyclic group comprises a substituted or unsubstituted 3- to 12-membered cycloalkyl group, a substituted or unsubstituted 3- to 12-membered heterocyclic group, a substituted or unsubstituted 6- to 10-membered aryl group or a substituted or unsubstituted 5- to 10-membered heteroaryl group, an organic macromolecular residue having a cyclic group, or an inorganic compound molecule residue having a cyclic group.

3. The compound of general formula (I) as claimed in claim 2, characterized in that: the organic macromolecular residue having a cyclic group comprises a cyclodextrin molecular residue.

4. The compound of general formula (I) according to claim 2, characterized in that: the inorganic compound molecular residue having a cyclic group comprises a cage-type polysilsesquioxane molecular residue.

5. The compound of general formula (I) according to claim 2, characterized in that: the structural unit having a cyclic group is selected from substituted or unsubstituted phenyl groups.

6. The compound represented by the general formula (I) according to claim 1, characterized in that the compound is a compound represented by the following formula:

.

7. A stereoisomer, tautomer, N-oxide, hydrate, solvate or pharmaceutically acceptable salt of the compound represented by general formula (I) as claimed in any one of claims 1 to 6.

8. A star-shaped β-antimicrobial glycopeptide, characterized in that the outer layer of the star-shaped β-antimicrobial glycopeptide is a helical glycopeptide block, the inner layer is a positively charged polydimethylamino beta-lactam block, and the structure of the star-shaped β-antimicrobial glycopeptide is as shown in general formula (I):

Formula (I)

Wherein, Core is a structural unit having a cyclic group;

n is 0~6, m is 3~100, x and y are 1~50.

9. The star-shaped β-antimicrobial glycopeptide according to claim 8, characterized in that the source of the glycopeptide block comprises monosaccharides such as glucose, galactose, mannose, altrose, aminoglucose, aminogalactose, aminomannose or disaccharide maltose.

10. A method for preparing the compound represented by general formula (I) according to claim 1, characterized in that the method comprises:

(i) according to reaction formula a, a precursor compound containing the core is polymerized with a compound represented by formula (II) and a compound represented by formula (III) to obtain a polymer represented by formula (IV);

Reaction formula a

(ii) According to reaction formula (b), deprotect the polymer represented by formula (IV)

Reaction equation b.

11. The method of claim 10, wherein step (a) comprises preparing the protective polymer in the presence of lithium bis(trimethylsilyl)amide.

12. The method of claim 10, wherein step (b) comprises: deprotecting the protected polymer under sodium and liquid ammonia conditions.

13. A pharmaceutical composition, characterized in that it comprises:

The compound represented by general formula (I) according to any one of claims 1 to 6 or a pharmaceutically acceptable salt thereof,

Or, the star-shaped β-antimicrobial glycopeptide according to any one of claims 8 to 9; and

A pharmaceutically acceptable carrier.

14. The pharmaceutical composition according to claim 13, characterized in that: the pharmaceutical composition further comprises other antibacterial agents.

15. The pharmaceutical composition according to claim 14, characterized in that: the other antibacterial agents include ampicillin, cloxacillin, oxacillin, piperacillin, cephalosporins, carbapenems, glycopeptides, macrolides, quinolones, tetracyclines, aminoglycosides, rifampicin, ciprofloxacin, levofloxacin, piperacillin, co-trimoxazole, gentamicin, lobramycin, erythromycin ethylsuccinate, erythromycin, clarithromycin, neomycin, spiramycin, acetylspiramycin, chloramphenicol, trimethoprim, sulfamethoxazole, carbenicillin, polymyxin B, colistin, amikacin, kanamycin, neomycin, Netilmicin, streptomycin, tobramycin, paromomycin, geldanamycin, herbimycin, loracarbef, doripenem, cilastatin, cefadroxil, cephalothin, cephalexin, cefprozil, cefuroxime, cefixime, cefdinir, cefditoren, cefpodoxime, ceftibuten, ceftizoxime, cefepime, teicoplanin, vancomycin, roxithromycin, acetylcholine Any one or more combinations of oxaliplatin, telithromycin, spectinomycin, amoxicillin, carbenicillin, dicloxacillin, flucloxacillin, mezlocillin, methicillin, nafcillin, penicillin, ticarcillin, bacitracin, enoxacin, gatifloxacin, moxifloxacin, norfloxacin, trovafloxacin, mafenide, sulfazosulfonamide, sulfacetamide, sulfamethoxazole, sulfonamide, sulfasalazine, sulfisoxazole, trimethoprim-sulfamethoxazole, demeclocycline, doxycycline, minocycline, oxytetracycline, tetracycline, arsphenamine, clindamycin, lincomycin, ethambutol, fosfomycin, fusidic acid, furazolidone, isoniazid, linezolid, bifenthrin suppository, mupirocin, nitrofurantoin, pyrazinamide, quinupristin/dalfopristin, isoflavone, and tinidazole.

16. The pharmaceutical composition according to claim 15, characterized in that the cephalosporin comprises any one or more combinations of cefaclor, cefmandole, cefazolin, cefoperazone, cefotaxime, cefoxitin, ceftazidime and ceftriaxone.

17. The pharmaceutical composition according to claim 15, characterized in that the carbapenems include any one or more combinations of imipenem and meropenem.

18. Use of the compound represented by general formula (I) according to any one of claims 1 to 6 or a pharmaceutically acceptable salt thereof or the pharmaceutical composition according to any one of claims 13 to 17 as an antibacterial agent.

19. The use according to claim 18, characterized in that the other antibacterial agents contained in the pharmaceutical composition include antibiotics against Gram-positive bacteria, and the antibacterial range of the antibacterial agent includes Gram-negative bacteria.

20. Use of the compound of general formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 6, the star-shaped β-antimicrobial glycopeptide according to any one of claims 8 to 9, or the pharmaceutical composition according to any one of claims 13 to 17 in the preparation of a medicament for treating or preventing bacterial infection or a disease caused by the bacterial infection.

21. The use according to claim 20, characterized in that the bacteria include at least one of multi-drug resistant bacteria and sensitive bacteria.

22. Use of the compound of general formula (I) according to any one of claims 1 to 6 or a pharmaceutically acceptable salt thereof, the star-shaped β-antimicrobial glycopeptide according to any one of claims 8 to 9, or the pharmaceutical composition according to any one of claims 13 to 17 as a cellular efflux pump inhibitor.

23. Use of the compound of general formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 6, the star-shaped β-antimicrobial glycopeptide according to any one of claims 8 to 9, or the pharmaceutical composition according to any one of claims 13 to 17 as a bacterial membrane permeabilizing agent.