Daptomycin modifier as well as synthesis method and application thereof

Abstract

The invention discloses a daptomycin modifier as well as a synthesis method and application thereof, and the daptomycin modifier is obtained by modifying a Trp1 site of daptomycin. The structure is shown as a general formula (I). Wherein R is an aromatic group or an aromatic sulfur group with alkyl, alkyl substituent, alkoxy, hydroxyl, nitryl or halogen substituent. The synthesis method is simple and easy to obtain, the synthesis efficiency is high, and the time cost and raw material cost are reduced. An in-vitro antibacterial experiment, a hemolytic activity experiment and an in-vitro serum stability experiment show that the synthesized daptomycin modifier is more effective in resisting gram-positive bacteria, particularly MRSA and biological membrane infection caused by the MRSA, is safe, low in toxicity and good in stability, has a good application prospect in the aspect of preparing clinical antibacterial drugs, and has a wide application prospect. The compound is expected to become a novel antibiotic candidate drug.

Description

Technical Field

[0001] This invention belongs to the field of medicinal chemistry technology, specifically relating to a class of daptomycin modifiers and their synthesis methods. This invention also relates to the application of these daptomycin modifiers in the preparation of drugs for treating / preventing drug-resistant bacterial infections and biofilm infections. Background Technology

[0002] Bacterial infections have long posed a serious threat to global health, becoming the second leading cause of death after ischemic heart disease. Simultaneously, with the widespread use of antibiotics globally, bacterial resistance has become an increasingly prominent issue. Biofilms are one of the main causes of bacterial resistance. Compared to planktonic cells, cells in biofilms are highly resistant to environmental stresses, disinfectants, antibiotic treatment, and host immune defenses, leading to recurrent and persistent biofilm infections. A US NIH survey found that up to 80% of human bacterial infections are related to biofilms. Currently, there are no ideal drugs to effectively treat drug-resistant infections caused by bacterial biofilms, making the development of new antibiotics an urgent priority.

[0003] Daptomycin, a calcium-dependent lipopeptide antibiotic, is one of the leading antibiotics to enter the market since 2000. It was initially discovered by researchers at Eli Lilly in cultures of the soil bacterium *Streptomyces roseosus*. In 2003, daptomycin was approved by the FDA for the treatment of complicated skin and soft tissue infections caused by various Gram-positive pathogens, making it the first lipopeptide antibiotic available clinically. In 2006, daptomycin was approved for the treatment of endocarditis and bacteremia caused by Gram-positive pathogens, particularly infections caused by *Staphylococcus aureus* (including MRSA). However, with the use of daptomycin, resistant strains have emerged. Therefore, structural modification of daptomycin to develop new next-generation antibiotics with activity against resistant bacteria and their biofilms has significant clinical value. Summary of the Invention

[0004] Based on the above, the purpose of this invention is to provide a class of daptomycin modifiers to solve the technical problem that the emergence of daptomycin-resistant bacteria renders existing daptomycin ineffective, thereby causing new bacterial infections.

[0005] Another object of the present invention is to provide a method for synthesizing the above-mentioned daptomycin modified compounds.

[0006] Another object of the present invention is to provide the use of daptomycin modified products in the preparation of clinical antibacterial drugs.

[0007] To achieve its purpose, the present invention adopts the following technical solution:

[0008] I. Daptomycin Modified Compounds and Their Synthesis

[0009] The present invention provides a class of daptomycin modified compounds, the structure of which is shown in general formula (Ⅰ);

[0010]

[0011] Wherein, R is an aromatic group or aromatic sulfur group having alkyl, alkyl substituent, alkoxy, hydroxy, nitro or halogen substituent.

[0012] The synthesis method of the above-mentioned daptomycin modified product is as follows:

[0013] (I) Synthesis of aryl-modified daptomycin derivatives

[0014] Daptomycin (1 eq.), phenylboronic acid modifier (2-10 eq.), palladium acetate (5-100 mol%), and copper acetate (5-100 mol%) were placed in a dry reaction tube and reacted with acetic acid as solvent. After the reaction was completed, the mixture was concentrated by LC-MS and purified by reversed-phase preparative high-performance liquid chromatography to obtain daptomycin modifier 1. The synthetic route is as follows:

[0015]

[0016] Among them, R 1 It is any one of the following: saturated or unsaturated hydrocarbon group, halogen, haloalkyl group, aryl or substituted aryl group, nitro group, alkoxy group, hydroxyl group, hydroxyalkyl group, carboxyl group or carboxylalkyl group with H or C < 6 at any position (ortho, meta, or para).

[0017] Preferably, the amount of acetic acid added is such that the concentration of daptomycin is 0.01-0.1M.

[0018] Preferably, the LC-MS monitoring reaction conditions are: mobile phase A: 0.1% (v / v) formic acid aqueous solution, mobile phase B: acetonitrile, and the reaction endpoint is the complete reaction of daptomycin. The mobile phase flow rate gradient is as follows:

[0019]

[0020] Preferably, the reverse-phase preparative high-performance liquid chromatography purification conditions are: mobile phase A: 0.1% trifluoroacetic acid acetonitrile solution (v / v) and mobile phase B: 0.1% trifluoroacetic acid aqueous solution (v / v).

[0021] The velocity gradient of the mobile phase is as follows:

[0022]

[0023] (II) Synthesis of aryl sulfide-modified daptomycin derivatives

[0024] Daptomycin (1 eq.), thiophenol substrate (2-10 eq.), TCEP (2-5.0 eq.), and Rose Bengal (5-50 mol%) were placed in a dry quartz reaction tube, and ultra-dry solvent DMSO was added. The mixture was stirred under blue light at 400-450 nm. After the reaction was completed, the mixture was concentrated by LC-MS monitoring, and then purified by reversed-phase preparative high-performance liquid chromatography to obtain daptomycin modified compound 2. The synthetic route is as follows:

[0025]

[0026] Among them, R 2 It is any one of the following: saturated or unsaturated hydrocarbon group, halogen, haloalkyl group, aryl or substituted aryl group, nitro group, alkoxy group, hydroxyl group, hydroxyalkyl group, carboxyl group or carboxylalkyl group with H or C < 6 at any position (ortho, meta, or para).

[0027] Preferably, the amount of DMSO added is such that the daptomycin reaction concentration is 0.01-0.1M.

[0028] Preferably, the LC-MS monitoring reaction conditions are: mobile phase A: 0.1% (v / v) formic acid aqueous solution, mobile phase B: acetonitrile, and the reaction endpoint is the complete reaction of daptomycin. The mobile phase flow rate gradient is as follows:

[0029]

[0030] Preferably, the reversed-phase preparative high-performance liquid chromatography purification conditions are as follows: mobile phase A: 0.1% (v / v) trifluoroacetic acid acetonitrile solution, mobile phase B: 0.1% (v / v) trifluoroacetic acid aqueous solution, and the mobile phase flow rate gradient is as follows:

[0031]

[0032] The above-mentioned daptomycin modifiers can be prepared into pharmaceutical compositions comprising the daptomycin modifier, a pharmaceutically acceptable salt thereof, a solvate, a stereoisomer thereof or a prodrug thereof, and a pharmaceutically acceptable carrier or excipient.

[0033] II. Application of Daptomycin Modified Compounds in the Preparation of Clinical Antibacterial Drugs

[0034] 1. In vitro antibacterial test

[0035] The minimum inhibitory concentrations (MICs) of daptomycin modified compounds against Staphylococcus aureus, methicillin-resistant Staphylococcus aureus, Enterococcus faecalis, Enterococcus faecium, Bacillus subtilis, and Staphylococcus epidermidis were determined using the micro-dilution method. Daptomycin and vancomycin were used as positive controls. Results are shown in [Figure number missing]. Figure 2 .

[0036] Figure 2 The results showed that the daptomycin modified product provided by this invention has strong anti-Gram-positive bacterial activity. The aryl modification, especially the halogenated aryl group, showed several times the antibacterial effect against drug-resistant Staphylococcus aureus, Enterococcus faecalis, and Enterococcus faecium compared to daptomycin. In particular, compared to daptomycin, vancomycin, tigecycline, and amoxicillin, the daptomycin modified product provided by this invention exhibited excellent antibacterial activity against clinically isolated drug-resistant bacteria, as shown in the results. Figure 3 .

[0037] 2. Hemolytic activity test

[0038] To test the toxicity of daptomycin and its modifications to mammalian cells, this invention determined the hemolysis of mouse erythrocytes after incubation at 37°C for 1 hour with daptomycin and its modifications. These modifications contain various types of aryl groups, and the substituents on the aryl groups include methyl, chloro, bromo, fluoro, nitro, phenyl, etc. Figure 4 The results showed that the hemolytic activity of the daptomycin modified product provided by this invention was less than 1% at a concentration of 256 μg / mL. This result indicates that the daptomycin modified product provided by this invention has very low toxicity and excellent drug development potential.

[0039] 3. In vitro serum stability test

[0040] To examine whether the in vitro serum stability of daptomycin-modified products changed after modification, this invention determined the residual percentage of daptomycin, the 1c-modified product, and the 1i-modified product in 95% mouse serum after incubation for different time periods. Figure 5 As shown, with prolonged incubation time, the serum stability of 1c and 1i was comparable to that of the commercially available drug daptomycin.

[0041] 4. Anti-biofilm effect experiment

[0042] Bacteria were cultured in nutrient broth at 37°C in a shaker until the logarithmic growth phase, and then diluted to a bacterial suspension of 1.0 × 10⁶ CFU / mL with TSBG medium. The test substance was diluted twofold to a concentration gradient of 4-64 μg / mL using TSBG medium, with polymyxin B as an antibiotic control. Samples were added to 96-well plates in groups: the experimental group received equal volumes of different concentrations of peptide drug and bacterial suspension; the positive control group received equal volumes of TSBG medium and bacterial suspension; and the negative control group received only TSBG medium. The plates were incubated at 37°C for 24 h to allow biofilm formation. The 96-well plates were then removed, surface-dwelling bacteria were removed, and the plates were gently washed with PBS buffer. The plates were fixed with anhydrous methanol for 15 min, dried, and then stained with 0.1% crystal violet for 15 min. The crystal violet stain was removed, and the plates were washed 2-3 times with deionized water. Finally, 95% ethanol was added and the plate was incubated for 15 min. The absorbance at 595 nm was then measured.

[0043] Biofilm formation inhibition rate (%) = [1 - (OD595 of experimental group - OD595 of negative control group) / (OD595 of positive control group - OD595 of negative control group)] × 100%.

[0044] The daptomycin modified product provided by this invention exhibits significantly superior anti-biofilm activity compared to the positive control drug daptomycin, as shown in the following results. Figure 6 As shown.

[0045] The beneficial effects of this invention are as follows:

[0046] This invention modifies the Trp1 site of daptomycin to obtain a class of daptomycin-modified compounds. The synthesis method is simple, readily available, and highly efficient, reducing time and raw material costs. In vitro antibacterial experiments, hemolytic activity experiments, and in vitro serum stability experiments show that the daptomycin-modified compounds synthesized in this invention are more effective against Gram-positive bacteria, especially MRSA and its induced biofilm infections, exhibiting good safety, low toxicity, and stability. They show great promise for the preparation of clinical antibacterial drugs and are expected to become candidate drugs for novel antibiotics. Attached Figure Description

[0047] Figure 1 Structural diagram of the daptomycin modified product of this invention;

[0048] Figure 2 Results of in vitro antibacterial activity tests of the compounds of this invention;

[0049] Figure 3 Results of anti-drug-resistant bacterial activity tests of some compounds in this invention against clinically isolated pathogens;

[0050] Figure 4 Some compounds in this invention exhibit hemolytic activity;

[0051] Figure 5 Serum stability test results of some compounds of this invention;

[0052] Figure 6 Experimental results of the anti-biofilm activity of some compounds in this invention;

[0053] Figure 7 Evaluation of the therapeutic activity of compound 1i in a wound infection model;

[0054] Figure 8 Evaluation of the therapeutic activity of compound 1i in a ductal biofilm model. Detailed Implementation

[0055] To make the advantages and technical solutions of the present invention clearer, the embodiments of the present invention will be described in detail below with reference to the examples. The described embodiments are only some embodiments of the present invention, and not all embodiments. Based on the embodiments of the present invention, all other implementation methods obtained by those skilled in the art without creative effort are within the scope of protection of the present invention.

[0056] Those skilled in the art will understand that the following embodiments are for illustrative purposes only and should not be construed as limiting the scope of the invention. Unless otherwise specified, specific conditions are applied under conventional conditions or conditions recommended by the manufacturer. Unless otherwise stated, all reagents and instruments used are commercially available.

[0057] Materials and Methods:

[0058] Unless otherwise specified, the experimental conditions and methods described in the following examples are conventional conditions and methods, and the reagents or instruments mentioned are all commercially available.

[0059] GraphPad Prism 8.0 software was used for data statistics and analysis. The data are expressed as mean ± standard deviation (Mean ± SD). Significance differences were analyzed by one-way ANOVA and Tukey test (***P < 0.001, **P < 0.01, *P < 0.05).

[0060] The synthesis of the daptomycin modified compound of the present invention will be further illustrated below through specific embodiments.

[0061] Example 1

[0062] Daptomycin (0.03 mmol), phenylboronic acid (10 equiv), palladium acetate catalyst (30 mol%), and copper acetate (60 mol%) were weighed into a dry reaction tube. 1.0 mL of acetic acid was added as a solvent. After stirring at room temperature for 16 h (the reaction was monitored to be complete by an Agilent 6100 LC-MS; mobile phase A: 0.1% formic acid aqueous solution; mobile phase B: acetonitrile; flow rate as described in section (I) of the invention), the mixture was concentrated and purified by reversed-phase preparative high-performance liquid chromatography (RP-HPLC). Mobile phase A: 0.1% trifluoroacetic acid acetonitrile solution; mobile phase B: 0.1% trifluoroacetic acid aqueous solution; flow rate as described in section (II) of the invention, yielding daptomycin modified compound 1a with a yield of 57%. The synthetic methods and implementation schemes for compounds 1a-1u are shown in Table 1, and the detailed structures are described in [details omitted]. Figure 1 A. Table 1 shows the theoretical m / z, measured m / z, and purity of the compounds synthesized in Example 1.

[0063] Table 1 Characterization of the compounds synthesized in Example 1

[0064]

[0065]

[0066] Example 2

[0067] 32.4 mg (0.02 mmol) of daptomycin, 5 equiv of thiophenol substrate, 28.7 mg (5.0 equiv) of TCEP, and 2.03 mg (10 mol%) of Rose Bengal catalyst were weighed into a dry quartz reaction tube. Finally, 0.5 mL of DMSO solvent was added. The mixture was stirred under 440 nm blue light, and the reaction progress was monitored using an Agilent 6100 LC-MS until the daptomycin reaction was complete. Mobile phase A: 0.1% (v / v) formic acid aqueous solution; mobile phase B: acetonitrile; flow rate as described in section (I) of the invention. The mixture was purified by reversed-phase preparative high-performance liquid chromatography. Mobile phase A: 0.1% (v / v) trifluoroacetic acid acetonitrile solution; mobile phase B: 0.1% (v / v) trifluoroacetic acid aqueous solution; flow rate as described in section (II) of the invention, yielding daptomycin modified compound 2. The synthetic schemes for compounds 2a-2r are shown in Table 2, and the detailed structures are described in […]. Figure 1 B. Table 2 shows the theoretical m / z, measured m / z, and purity of the compounds synthesized in Example 2.

[0068] Table 2 Characterization of the compounds synthesized in Example 2

[0069]

[0070]

[0071] Example 3

[0072] The compounds obtained in Examples 1 and 2 were used as test substances for in vitro antibacterial activity testing. The minimum inhibitory concentration (MIC) of the antimicrobial peptides against Gram-positive bacteria (Staphylococcus aureus, Bacillus subtilis, Staphylococcus epidermidis, Enterococcus faecalis, methicillin-resistant Staphylococcus aureus, and clinically resistant strains) was determined using the classic micro-dilution serial dilution method. The experiment was repeated in triplicate with the antibiotics daptomycin and vancomycin as positive controls. Results are shown in the table below. Figure 2 , Figure 3 .

[0073] Depend on Figure 2 , Figure 3 The results show that the daptomycin modified by this invention has stronger antibacterial activity than the positive control drugs daptomycin and vancomycin. In particular, against Gram-positive drug-resistant bacteria, especially clinically isolated MRSA-resistant bacteria, the daptomycin modified by this invention exhibits significant antibacterial superiority, outperforming existing clinical drugs daptomycin, vancomycin, tigecycline, and amoxicillin.

[0074] Example 4

[0075] Hemolytic activity assay

[0076] Mouse red blood cells (RBCs) were suspended in PBS to a final concentration of 8% (v / v). The test compounds were diluted in PBS to different concentrations. In a 96-well plate, 100 μL of the RBC suspension was mixed with 100 μL of a simulant solution. The plates were incubated at 37°C for 1 h. After incubation, the mixture was centrifuged, and 100 μL of the supernatant was carefully transferred to a new 96-well plate. The absorbance was measured at 490 nm. PBS and 1% Triton X-100 were used as negative and positive controls, respectively. Results are as follows: Figure 4 As shown, the daptomycin modified product provided by the present invention has hemolytic activity similar to that of the clinical drug daptomycin and has a high safety profile.

[0077] Example 5

[0078] Serum stability assay

[0079] Blood was collected from mouse eyeballs. The blood was centrifuged twice, and the supernatant was collected as serum. The peptide drug was prepared into a 10 mM solution using PBS. The peptide drug was mixed with 100% mouse serum at a ratio of 5:95 (v / v). After mixing, the mixture was incubated at 37°C. At 0 h, 2 h, 4 h, 8 h, 12 h, 24 h, and 48 h, 80 μL of the solution was collected, and an equal volume of ice-cold acetonitrile was added. The reaction was terminated after 2 min of incubation. The mixture was centrifuged twice at 10000 rpm for 10 min each time, and the supernatant was collected. 100 μL of the supernatant was analyzed using RP-HPLC to calculate the retention rate. The results were statistically analyzed and plotted using GraphPad Prism software. Each experiment was repeated three times independently. The results are shown below. Figure 5 As shown, the daptomycin modified product provided by the present invention has similar serum stability to the clinical drug daptomycin and high drugability.

[0080] Example 6

[0081] Anti-biofilm activity assay

[0082] Bacteria were cultured in nutrient broth at 37°C in a shaker until the logarithmic growth phase, and then diluted to a bacterial suspension of 1.0 × 10⁶ CFU / mL with TSBG medium. The test substance was diluted twofold to a concentration gradient of 4-64 μg / mL using TSBG medium, with polymyxin B as an antibiotic control. Samples were added to 96-well plates in groups: the experimental group received equal volumes of different concentrations of peptide drug and bacterial suspension; the positive control group received equal volumes of TSBG medium and bacterial suspension; and the negative control group received only TSBG medium. The plates were incubated at 37°C for 24 h to allow biofilm formation. The 96-well plates were then removed, surface-dwelling bacteria were removed, and the plates were gently washed with PBS buffer. The plates were fixed with anhydrous methanol for 15 min, dried, and then stained with 0.1% crystal violet for 15 min. The crystal violet stain was removed, and the plates were washed 2-3 times with deionized water. Finally, 95% ethanol was added and the plate was incubated for 15 min. The absorbance at 595 nm was then measured.

[0083] Biofilm formation inhibition rate (%) = [1 - (OD595 of experimental group - OD595 of negative control group) / (OD595 of positive control group - OD595 of negative control group)] × 100%.

[0084] like Figure 6 As shown, the daptomycin modified by this invention exhibits anti-biofilm activity that is significantly superior to the positive control drug daptomycin.

[0085] Example 7

[0086] Therapeutic effect of MRSA-induced wound biofilm infection model

[0087] Forty-eight BALB / c mice were randomly assigned to six groups (n=8). After anesthesia, two full-thickness excision wounds (5 mm in diameter) were created on the dorsal skin of each mouse. Each wound was infected with MRSA48 (CFU / mL in 5 × 10⁶ TSBG). At 1, 24, and 48 hours after infection, wounds in the normal and model groups were treated with 20 μL PBS, while the treatment groups received 1 ibuprofen (0.25 mg / kg, 1 mg / kg) or Dap (0.25 mg / kg, 1 mg / kg). Seventy-two hours after infection, dressings and infected skin tissue were collected for bacterial colonization, and wound samples were subjected to H&E staining for histological evaluation. Inflammatory cytokines at the wound site were quantified using an ELISA kit.

[0088] The results are as follows Figure 7 As shown, the daptomycin modified product provided by this invention exhibits significantly superior anti-MRSA biofilm infection activity compared to the positive control drug daptomycin, thereby producing a significant wound-healing effect and demonstrating promising clinical application prospects.

[0089] Example 8

[0090] Therapeutic effect of MRSA-induced catheter biofilm infection model

[0091] Forty-eight male BALB / c mice were randomly divided into six groups (n=8). A 1 cm catheter was implanted subcutaneously, and 100 μL of LMRSA 48 (1×10⁶ CFU / mL) was injected into TSBG. For the biofilm eradication model, the catheter was pre-incubated in the same bacterial suspension for 24 hours, washed to remove planktonic cells, and then implanted. At 1 hour, 24 hours, and 48 hours after infection, the catheters in the normal and model groups were injected with 100 μL of PBS, while the treatment groups received 1i (0.25 mg / kg, 1 mg / kg) or Dap (0.25 mg / kg, 1 mg / kg). Seventy-two hours after infection, the catheters were removed and subjected to ultrasound therapy. The bacterial load was then quantified.

[0092] The results are as follows Figure 8 As shown, the daptomycin modified by this invention exhibits significantly better anti-catheter biofilm activity than the positive control drug daptomycin in animals, demonstrating promising clinical application prospects.

Claims

1. A class of daptomycin-modified compounds, characterized in that: Its structure is shown in general formula (Ⅰ); Wherein, R is an aromatic group or aromatic sulfur group having alkyl, alkyl substituent, alkoxy, hydroxy, nitro or halogen substituent.

2. The method for synthesizing the daptomycin modified compound as described in claim 1, characterized in that: When R is an aromatic group having alkyl, alkyl substituent, alkoxy, hydroxy, nitro, or halogen substituent, the synthesis method is as follows: Daptomycin (1 eq.), phenylboronic acid modifier (2-10 eq.), palladium acetate (5-100 mol%), and copper acetate (5-100 mol%) are placed in a dry reaction tube, and the reaction is carried out in acetic acid as solvent. After the reaction is completed, the mixture is concentrated by LC-MS monitoring, and purified by reversed-phase preparative high-performance liquid chromatography to obtain daptomycin modifier 1. The synthetic route is as follows: When R is an aromatic sulfide group having alkyl, alkyl substituent, alkoxy, hydroxy, nitro, or halogen substituent, the synthesis method is as follows: Daptomycin (1 eq.), thiophenol substrate (2-10 eq.), TCEP (2-5.0 eq.), and Rose Bengal (5-50 mol%) are placed in a dry quartz reaction tube, and ultra-dry solvent DMSO is added. The reaction is stirred under blue light at 400-450 nm. After the reaction is completed, the mixture is concentrated by LC-MS monitoring, and then purified by reversed-phase preparative high-performance liquid chromatography to obtain daptomycin modified compound 2. The synthetic route is as follows: Among them, R 1 R 2 All of them are any one of the following: saturated or unsaturated hydrocarbon groups, halogens, haloalkanes, aryl or substituted aryl groups, nitro groups, alkoxy groups, hydroxyl groups, hydroxyalkyl groups, carboxyl groups or carboxylalkyl groups, with H or C < 6 at any position (ortho, meta, or para).

3. The method for synthesizing the daptomycin modified compound as described in claim 2, characterized in that: The amount of acetic acid added is such that the concentration of daptomycin is 0.01-0.1M.

4. The method for synthesizing the daptomycin modified compound as described in claim 2, characterized in that: The amount of DMSO added is such that the concentration of daptomycin is 0.01-0.1M.

5. The method for synthesizing the daptomycin modified compound according to any one of claims 2-4, characterized in that: The reaction endpoint was determined by LC-MS monitoring when the daptomycin raw material was completely consumed.

6. The method for synthesizing the daptomycin modified compound as described in claim 5, characterized in that: The LC-MS monitoring reaction conditions were as follows: mobile phase A: 0.1% formic acid aqueous solution (volume fraction) and mobile phase B: acetonitrile.

7. The method for synthesizing the daptomycin modified compound as described in claim 6, characterized in that: The reversed-phase preparation high-performance liquid chromatography purification is performed under the following conditions: mobile phase A: 0.1% trifluoroacetic acid acetonitrile solution (v / v) and mobile phase B: 0.1% trifluoroacetic acid aqueous solution (v / v).

8. A pharmaceutical composition, characterized in that, The composition comprises the daptomycin modifier as described in claim 1, a pharmaceutically acceptable salt thereof, a solvate thereof, a stereoisomer thereof or a prodrug thereof, and a pharmaceutically acceptable carrier or excipient.

9. The use of the tylosin-modified compound as described in claim 1 in the preparation of clinical antibacterial drugs, characterized in that, The antibacterial drug is an anti-Gram-positive drug-resistant bacteria drug or an anti-biofilm infection drug.

10. The use of the pharmaceutical composition of claim 8 in the preparation of a clinical antimicrobial drug, wherein the antimicrobial drug is an anti-Gram-positive drug-resistant bacteria drug or an anti-biofilm infection drug.

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