Aromatic pleuromutilin derivative with antibacterial effect as well as preparation method and application of aromatic pleuromutilin derivative

Abstract

The invention belongs to the field of medicinal chemistry, and discloses an aromatic pleuromutilin derivative with an antibacterial effect as well as a preparation method and application of the aromatic pleuromutilin derivative. The pleuromutilin is structurally modified, aromatic group modification is further increased through a reductive amination method after mercaptoethylamine is introduced into a C-14 side chain, and the structural formula of the pleuromutilin is shown in the specification. Research on an antibacterial mechanism finds that the series of derivatives can effectively interfere with expression of bacterial protein and show unique and excellent antibacterial activity, and the pleuromutilin can be applied to preparation of antibacterial agents. Compared with pleuromutilin in the prior art, most of the pleuromutilin compounds have antibacterial activity on staphylococcus aureus, escherichia coli, salmonella, micrococcus luteus and enterococcus faecalis which are common in in-vitro clinical application, hardly generate drug resistance, have stable safety and are expected to be further optimized into lead compounds of novel antibiotics.

Description

Technical Field

[0001] This invention belongs to the field of medicinal chemistry and relates to truncated pleurotin derivatives, their synthesis methods, and applications. Background Technology

[0002] Antibiotics are the foundation of modern medicine. For nearly 100 years, they have prevented countless deaths caused by bacterial infections and promoted the development of modern medicine. However, due to the irrational use and even abuse of antibiotics, antibiotic resistance (AMR) is on the rise. Antibiotic resistance has become a serious existential threat to the fields of medicine and public health in the 21st century. Antibiotics are becoming increasingly ineffective, threatening global health. The number of people dying directly from drug-resistant bacterial infections worldwide is rising year by year, and an increasing number of deaths are related to drug-resistant bacteria. Developing new antibiotics to solve the problem of bacterial resistance is urgently needed. The emergence of methicillin-resistant Staphylococcus aureus (MRSA) has significantly increased the incidence of bacterial infections and is becoming increasingly prevalent in community and hospital settings, causing great distress to doctors and patients. Society urgently needs the development of new antibiotics.

[0003] Pleurotus truncatedis is a tricyclic diterpenoid antibiotic extracted from Basidiomycetes. It has a fused 5-6-8 tricyclic structure, and its unique structural type endows it with broad-spectrum antibacterial properties. The molecular structure is shown below:

[0004] As a natural tricyclic diterpenoid compound, truncated pleurotin is a protein synthesis inhibitor that acts on the 50S subunit of bacterial ribosomes. It exerts its antibacterial effect by binding to the V domain of peptidyl transferase, thereby blocking bacterial protein synthesis. It is effective against Gram-positive bacteria and mycoplasma infections, and its unique antibacterial mechanism makes it difficult to develop cross-resistance with other antibiotics. However, its antibacterial activity against Gram-negative bacteria and drug-resistant bacteria is generally low. Currently, four types of truncated pleurotin are marketed: tiamulin, vornimulin, retamorin, and lefamorin. Truncated pleurotin has successfully transitioned from animal to human use. The goal of structural modification of truncated pleurotin is to simultaneously improve its antibacterial activity against Gram-negative bacteria and drug-resistant bacteria while maintaining its high antibacterial activity against Gram-positive bacteria. Its mechanism of action mainly involves specifically binding to the peptidyl transferase center of the bacterial ribosomal 50S subunit. By simultaneously occupying the A and P sites in its spatial conformation, it effectively blocks substrate localization and transfer during peptide bond formation, thereby inhibiting bacterial protein biosynthesis. Studies have shown that the main site of antibacterial activity of truncated pleurotin is located in its tricyclic core, and modification of the C-14 side chain can significantly enhance its antibacterial activity. Based on the characteristics of truncated pleurotin, modifying it to develop novel antibiotic drugs has potential pharmaceutical application value. Summary of the Invention

[0005] Therefore, this invention modifies truncated pleurotin and screens out truncated pleurotin derivatives containing aromatic heterocycles with good antibacterial activity. The purpose of this invention is to provide a novel truncated pleurotin derivative.

[0006] Another object of the present invention is to provide a method for synthesizing such truncated pleurotin derivatives.

[0007] Another object of the present invention is to provide the application of such truncated pleurotin derivatives.

[0008] To achieve the objectives of this invention, while ensuring drug-like properties, the invention modifies the truncated C-14 side chain of pleurotin, keeping the sulfide and basic amino groups introduced into the C-14 side chain unchanged. The amino groups are further modified by introducing different types of aromatic aldehyde structures, enabling the target compound to interact with nucleotide residues through van der Waals forces, hydrogen bonds, and π-π conjugation. This provides a theoretical basis and new ideas for the subsequent development of novel truncated pleurotin derivatives with broad-spectrum, low-toxicity, and effective anti-drug-resistant bacteria.

[0009] This invention is achieved through the following technical solution: The structural formula of the truncated pleurotin derivative is:

[0010] R is selected from any of the following groups:

[0011] The second technical solution provided by this invention is: The synthetic method for the truncated pleurotin derivatives described above includes the following steps: (1) Synthesis of intermediates of truncated pleurotin derivatives Synthesis of S1 and intermediate 2 Weigh out the truncated pleurotin and add it to acetonitrile until completely dissolved. Add p-toluenesulfonyl chloride, triethylamine, and sodium hydroxide while stirring. Heat under reflux, extract, and dry to obtain the organic phase. Continue to concentrate the organic phase under reduced pressure and purify by column chromatography to obtain intermediate 2.

[0012] Synthesis of S2 and intermediate 3 In an organic solvent, intermediate 2 was added, followed by mercaptoethylamine and DBU (1,8-diazabicyclo[5.4.0]undec-7-ene), and the reaction was stirred in an ice bath. The pH was adjusted to 7-8 and the mixture was concentrated under reduced pressure. After extraction and drying, the organic phase was obtained. The organic phase was further concentrated under reduced pressure and purified by column chromatography to obtain intermediate 3.

[0013] (2) Synthesis of truncated pleurotin derivatives 4-1 to 4-19 Intermediate 3 and an aldehyde compound containing the linking group R were stirred in a solvent until completely dissolved. Formic acid solution and anhydrous magnesium sulfate were added, and the reaction was carried out at room temperature. Then, sodium cyanoborohydride was added in batches, and the reaction was carried out at room temperature again. After the reaction was completed, the solvent was concentrated under reduced pressure and evaporated to dryness. The solution was then extracted and dried. The crude product was subjected to column chromatography and freeze-dried to obtain the target compound.

[0014] The third technical solution provided by this invention is: The aforementioned application of truncated pleurotin derivatives in the preparation of drugs for the prevention and treatment of multidrug-resistant bacterial infections.

[0015] Beneficial effects of this invention: This invention utilizes p-toluenesulfonyl chloride to activate and truncate the hydroxyl group at the C-21 position of pleurotin, yielding intermediate 2. This intermediate then reacts with mercaptoethylamine hydrochloride under alkaline conditions to obtain the key intermediate 3. Intermediate 3 undergoes reductive amination reactions with different aromatic aldehydes to yield target compounds 4-1 to 4-19. Most of these compounds exhibit superior antibacterial activity compared to tiamulin. Compound 4-7 shows the best efficacy against Staphylococcus aureus. Studies of the antibacterial mechanism have revealed that this series of derivatives can effectively interfere with bacterial protein expression. Compound 4-7, in particular, exhibits unique and excellent antibacterial activity, shows almost no resistance development, and possesses stable safety, demonstrating potential value for antibiotic drug development and application. Attached Figure Description

[0016] Figure 1-3 The 1H NMR spectrum, 1C NMR spectrum, and mass spectrum of compound 4-1 of this invention are shown below. Figure 4-6 The 1H NMR spectrum, 1C NMR spectrum, and mass spectrum of compound 4-2 of this invention are shown below. Figure 7-9 The 1H NMR spectrum, 1C NMR spectrum, and mass spectrum of compound 4-3 of this invention are shown below. Figure 10-12 The 1H NMR spectrum, 1C NMR spectrum, and mass spectrum of compound 4-4 of this invention are shown below. Figure 13-15 The following are the 1H NMR, 1C NMR, and mass spectra of compounds 4-5 of this invention; Figure 16-18 The following are the 1H NMR, 1C NMR, and mass spectra of compounds 4-6 of this invention; Figure 19-21 The following are the 1H NMR, 1C NMR, and mass spectra of compounds 4-7 of this invention; Figure 22 The above are the 1H NMR spectra of compounds 4-8 of this invention; Figure 23-25The following are the 1H NMR, 1C NMR, and mass spectra of compounds 4-9 of this invention; Figure 26 The 1H NMR spectrum of compounds 4-10 of this invention; Figure 27-28 The carbon NMR spectrum and mass spectrum of compound 4-11 of this invention are shown below. Figures 29-30 The 1H NMR spectrum and mass spectrum of compounds 4-12 of this invention are shown below. Figures 31-33 The following are the 1H NMR, 1C NMR, and mass spectra of compounds 4-13 of this invention; Figures 34-35 The 1H NMR spectrum and mass spectrum of compounds 4-14 of this invention are shown below. Figures 36-38 The 1H NMR spectrum, 1C NMR spectrum, and mass spectrum of compounds 4-15 of this invention are shown below. Figures 39-41 The following are the 1H NMR, 1C NMR, and mass spectra of compounds 4-16 of this invention; Figures 42-44 The following are the 1H NMR, 1C NMR, and mass spectra of compounds 4-17 of this invention; Figures 45-46 The 1H NMR spectrum and mass spectrum of compounds 4-18 of this invention are shown below. Figures 47-49 The images show the 1H NMR, 1C NMR, and mass spectra of compounds 4-19 of this invention. Detailed Implementation

[0017] The present invention will now be described in detail. It should be understood that the embodiments described herein are for illustrative and explanatory purposes only and are not intended to limit the invention. Those skilled in the art will understand that various changes and modifications can be made to the present invention without departing from its spirit and scope.

[0018] Unless otherwise specified, the instruments, reagents, and materials used in the following embodiments are all conventional instruments, reagents, and materials already available in the prior art and can be obtained through legitimate commercial channels. The experimental methods and detection methods used in the following embodiments are also conventional experimental methods and detection methods already available in the prior art, unless otherwise specified.

[0019] Example 1: Synthesis method of truncated pleurotin derivative of the present invention 1. Synthetic method of truncated pleurotin derivative intermediates 1.1 Synthesis method of intermediate 2 Accurately weigh 2.0 g of truncated pleurotin and add it to 10 mL of acetonitrile until completely dissolved. While stirring, add 4.030 g of p-toluenesulfonyl chloride, 2.202 mL of triethylamine, and 845.36 mg of sodium hydroxide. Heat under reflux at 40-90 °C for 4-6 h, extract with dichloromethane, wash the extract mixture with saturated sodium chloride solution, and dry with anhydrous sodium sulfate. Continue to concentrate the organic phase under reduced pressure, purify by column chromatography with DCM:EA = 30:1~100:1 as the developing solvent. The obtained pure product was recrystallized to give a white solid with a yield of 78.5%. 1H NMR (400 MHz, Chloroform-d) δ 7.85 – 7.77 (m, 2H), 7.34 (d, J = 8.1 Hz, 2H), 6.40 (dd, J = 17.4, 11.0 Hz, 1H), 5.76 (d, J = 8.5 Hz, 1H), 5.35 – 5.15(m, 2H), 4.47 (s, 2H), 3.34 (dd, J = 10.6, 6.5 Hz, 1H), 2.44 (s, 3H), 2.32 –2.15 (m, 3H), 2.10 – 2.00 (m, 2H), 1.79 – 1.71 (m, 1H), 1.69 – 1.59 (m, 3H),1.53 – 1.31 (m, 8H), 1.24 (d, J = 16.1 Hz, 1H), 1.15 (s, 3H), 1.12 – 1.07 (m,1H), 0.87 (d, J = 7.0 Hz, 3H), 0.62 (d, J = 7.1 Hz, 3H). 1.2 Synthesis method of intermediate 3 In an organic solvent, 3.0 g of intermediate 2 was added, followed by 7.218 mg of mercaptoethylamine and 408.0 μL of DBU. The mixture was stirred in an ice bath for 6 h. The pH was adjusted to 7-8 with 10% HCl aqueous solution and concentrated under reduced pressure. Ethyl acetate was added for extraction, and the extract mixture was washed with saturated sodium chloride solution and dried with anhydrous sodium sulfate. The organic phase was further concentrated under reduced pressure and purified by column chromatography. The developing solvent was DCM:MeOH:NH3·H2O = 30:1:1%~100:1:1%. The pure product was recrystallized to obtain a white solid. 1H NMR (400MHz, Chloroform-d) δ 6.42 (dd, J = 17.5, 11.0 Hz, 1H), 5.71 (d, J = 8.5 Hz, 1H), 5.37 – 5.17 (m, 2H), 3.68 – 3.55 (m, 2H), 3.36 (dd, J = 10.6, 6.5 Hz, 1H), 2.33 (q, J = 6.9 Hz, 1H), 2.28 – 2.14 (m, 2H), 2.13 – 2.05 (m, 2H), 1.77(dd, J = 14.5, 3.3 Hz, 1H), 1.66 (q, J = 10.7, 10.2, 5.6 Hz, 2H), 1.57 – 1.38(m, 7H), 1.32 (d, J = 16.2 Hz, 1H), 1.20 – 1.08 (m, 4H), 0.88 (d, J = 7.0 Hz, 3H), 0.74 (d, J = 6.9 Hz, 3H). The synthesis route is as follows:

[0020] 2. Synthesis of truncated pleurotin derivatives 4-1 to 4-19 1 mmol of intermediate 3 and 1.1 mmol of an aldehyde compound containing a linking group R were stirred in 8-10 mL of methanol solution until completely dissolved. Then, 1.1 mmol of formic acid solution and 2 mmol of anhydrous magnesium sulfate were added. The mixture was reacted at room temperature for 5 h. Then, 1.5 mmol of sodium cyanoborohydride was added in batches, and the reaction was continued at room temperature for another 1 h. After the reaction was complete, the solvent was concentrated under reduced pressure and evaporated to dryness. The mixture was extracted with dichloromethane and saturated brine, and the lower organic phase was recovered and dried over anhydrous sodium sulfate. The crude product was subjected to column chromatography with a developing solvent of DCM:MeOH:NH3·H2O = 5:1:1%~30:1:1%. An oily product was obtained, which was freeze-dried to give a white solid 4-1~4-19.

[0021]

[0022] All synthetic end products were structurally identified by 1H NMR, 13C NMR and HRMS, and the structural characterization is as follows.

[0023] White powder, yield: 65%, melting point: 101.8~103.5℃. (400 MHz, Chloroform-d) δ 7.42 (d, J = 8.2 Hz, 2H), 7.18 (d, J = 8.0Hz, 2H), 6.45 (dd, J = 17.4, 11.0 Hz, 1H), 5.72 (d, J = 8.4 Hz, 1H), 5.36 –5.15 (m, 2H), 3.73 (s, 2H), 3.34 (d, J = 6.5 Hz, 1H), 3.11 (s, 2H), 2.84 –2.72 (m, 4H), 2.32 (p, J = 7.2 Hz, 1H), 2.27 – 2.13 (m, 2H), 2.13 – 2.02 (m,2H), 1.79 – 1.70 (m, 2H), 1.63 (dt, J = 14.5, 10.6 Hz, 3H), 1.53 (dd, J =13.5, 3.4 Hz, 1H), 1.48 – 1.40 (m, 4H), 1.38 – 1.23 (m, 3H), 1.15 (s, 4H), 0.87 (d, J = 7.0 Hz, 3H), 0.71 (d, J = 7.0 Hz, 3H). 13C NMR (101 MHz, Chloroform-d) δ 216.89, 168.72, 168.70, 138.91, 138.87, 138.85, 131.31,129.63, 129.59, 128.41, 123.48, 120.61, 117.02, 74.42, 69.17, 58.01, 57.99,52.51, 47.04, 45.27, 44.63, 43.74, 41.57, 36.57, 35.82, 34.28, 33.90, 32.65,30.24, 26.66, 26.21, 24.66, 16.68, 14.73,11.35. HRMS (ESI+) calculated forC13H44BrNO4S [ M + H ]+: 606.2253, found: 606.2256. Yellow powder, yield: 58%, melting point: 99.50~101.50℃. 1 H NMR (400 MHz, Chloroform- d ) δ 8.18 (s, 2H), 7.62 (s, 2H), 6.42(dd, J = 17.4, 11.0 Hz, 1H), 5.70 (d, J = 8.3 Hz, 1H), 5.23 (dd, J = 41.1, 14.2 Hz,2H), 4.05 (s, 2H), 3.36 (d, J = 6.3 Hz, 1H), 3.15 (s, 2H), 3.03 – 2.77 (m, 4H),2.37 – 1.97 (m, 5H), 1.70 (dd, J = 49.2, 12.5 Hz, 3H), 1.54 – 1.24 (m, 8H),1.15 (s, 4H), 0.89 (d, J = 6.9 Hz, 3H), 0.69 (d, J = 6.9 Hz, 3H). 13 C NMR (101 MHz,Chloroform- d ) δ 217.16, 169.08, 147.57, 147.26, 139.24, 128.85, 123.81, 117.30,74.71, 69.59, 58.27, 52.61, 47.49, 45.56, 44.93, 44.05, 41.87, 36.85, 36.13,34.57, 34.32, 32.88, 30.51, 26.96, 26.50, 24.95, 16.99, 15.01, 11.62. HRMS(ESI+) calculated for C 13 H 44 N2O6S [ M + H ] + : 573.2998, found: 573.2992. White powder, yield: 63%, melting point: 102.1~103.2℃. 1H NMR (400 MHz, Chloroform-d) δ 7.18 (d, J = 7.8 Hz, 2H), 7.11 (d, J= 7.7 Hz, 2H), 6.45 (dd, J = 17.4, 11.0 Hz, 1H), 5.72 (d, J = 8.5 Hz, 1H), 5.31 (dd, J = 10.9, 1.6 Hz, 1H), 5.17 (dd, J = 17.4, 1.6 Hz, 1H), 3.74 (s,2H), 3.34 (d, J = 6.5 Hz, 1H), 3.10 (s, 2H), 2.85 – 2.70 (m, 4H), 2.31 (s, 4H), 2.24 – 2.11 (m, 2H), 2.12 – 2.03 (m, 2H), 1.75 (dd, J = 14.5, 3.2 Hz,2H), 1.69 – 1.51 (m, 3H), 1.43 (s, 4H), 1.38 – 1.23 (m, 3H), 1.15 (s, 4H), 0.87 (d, J = 6.9 Hz, 3H), 0.71 (d, J = 6.9 Hz, 3H). 13C NMR (101 MHz, Chloroform-d) δ 217.09, 168.90, 139.09, 136.79, 136.62, 129.11, 128.08,117.15, 74.55, 69.30, 58.17, 53.07, 47.10, 45.43, 44.80, 43.91, 41.73, 36.75,35.99, 34.45, 33.98, 32.71, 30.40, 29.67, 26.83, 26.43, 24.83, 21.09, 16.82,14.89, 11.52. HRMS (ESI+) calculated for C32H47NO4S [ M + H ]+: 542.3304, found: 542.3309. White powder, yield: 69%, melting point: 102.3-103.5℃. 1 H NMR (400 MHz, Chloroform- d ) δ7.94 – 7.81 (m, 2H), 7.44 (s, 2H), 6.14 (dd, J = 17.7, 11.2 Hz, 1H), 5.55 (d, J = 8.1 Hz, 1H), 5.14 – 4.99 (m,2H), 3.77 (s, 2H), 3.42 (d, J = 5.9 Hz, 1H), 3.30 – 3.17 (m, 2H), 2.70 (s, 4H), 2.40 (s, 1H), 2.23 – 2.01 (m, 4H), 1.70 – 1.56 (m, 2H), 1.47 (d, J = 6.4 Hz, 1H), 1.41 (d, J = 13.2 Hz, 1H), 1.36 (s, 3H), 1.27 (t, J = 15.9 Hz, 3H), 1.05 (s, 4H), 0.82 (d, J = 6.9 Hz, 3H), 0.62 (d, J = 6.6 Hz, 3H). 13 C NMR (101 MHz, DMSO- D 6) δ 217.27, 168.48, 140.92, 129.39, 128.60, 115.18, 72.59, 69.49, 57.28, 51.20,47.12, 45.00, 44.05, 43.73, 41.48, 36.46, 36.40, 34.03, 33.60, 30.38, 30.14,28.59, 26.59, 24.51, 16.17, 14.58, 11.58. HRMS (ESI+) calculated for C 32 H 45 NO6S[M+H] + : 572.3046, found: 572.3039. White powder, yield: 55%, melting point: 99.7~101.3℃. 1 H NMR (400 MHz, Chloroform- d ) δ 7.38 – 7.25 (m, 5H), 6.45 (ddd,J = 19.0,11.0, 8.2 Hz, 1H), 5.72 (t, J = 8.2 Hz, 1H), 5.35 – 5.14 (m, 2H), 3.79 (s, 2H),3.36 (d, J = 6.5 Hz, 1H), 3.06 (d, J = 48.9 Hz, 2H), 2.86 – 2.67 (m, 4H), 2.34(q, J = 7.0 Hz, 1H), 2.25 – 2.14 (m, 2H), 2.11 – 2.03 (m, 2H), 1.76 (dt, J =14.3, 3.1 Hz, 1H), 1.62 (ddd, J = 22.6, 12.8, 6.3 Hz, 3H), 1.56 – 1.40 (m, 5H),1.39 – 1.20 (m, 3H), 1.13 (d, J = 21.1 Hz, 4H), 0.87 (dd, J = 7.1, 4.2 Hz, 3H),0.71 (dd, J = 10.8, 6.8 Hz, 3H). 13 C NMR (101 MHz, Chloroform- d ) δ 216.99, 216.93,168.77, 168.73, 139.67, 139.04, 138.95, 128.61, 128.28, 128.05, 128.03,127.96, 126.91, 126.81, 116.96, 74.38, 69.16, 58.02, 58.00, 57.84, 53.18,51.94, 47.01, 45.27, 44.63, 43.75, 43.69, 41.57, 41.54, 36.60, 36.58, 35.83,35.81, 34.29, 34.03, 33.83, 32.55, 30.26, 30.23, 27.02, 26.66, 26.31, 26.23,24.67, 16.67, 16.63, 14.76, 14.74, 11.37. HRMS (ESI+) calculated for C 31 H45 NO4S[ M + H ] + : 528.3148, found: 529.3104. White powder, yield: 70%, melting point: 92.7~94.8℃. 1H NMR (400 MHz, Chloroform-d) δ 7.45 (s, 1H), 7.28 (s, 4H), 6.46 (dd, J = 17.4, 11.1 Hz, 1H), 5.74 (d, J = 8.5 Hz, 1H), 5.38 – 5.16 (m, 2H),3.77 (s, 2H), 3.35 (d, J = 6.4 Hz, 1H), 3.14 (s, 2H), 2.90 – 2.71 (m, 4H),2.33 (t, J = 6.9 Hz, 1H), 2.26 – 2.21 (m, 1H), 2.17 (s, 2H), 2.07 (d, J =20.5 Hz, 2H), 1.77 (d, J = 14.5 Hz, 1H), 1.69 – 1.59 (m, 2H), 1.55 (d, J =14.4 Hz, 1H), 1.45 (d, J = 5.5 Hz, 4H), 1.36 (d, J = 18.8 Hz, 2H), 1.32 –1.23 (m, 3H), 1.18 – 1.09 (m, 4H), 0.88 (d, J = 7.0 Hz, 3H), 0.72 (d, J = 6.9Hz, 3H). 13C NMR (101 MHz, DMSO-D6) δ 215.97, 167.23, 166.87, 139.62, 136.90, 136.84, 127.56, 127.10, 117.48, 113.88, 71.31, 68.09, 56.00, 50.46, 46.15, 43.71, 42.75, 42.46, 40.18, 40.15, 38.86, 38.76, 38.65, 38.44, 38.23, 38.02, 37.91, 37.82, 37.72, 37.61, 35.16, 35.12, 32.74, 32.34, 30.22, 28.86, 27.30, 25.30, 23.22, 22.69, 14.86, 14.80, 13.28, 10.29. HRMS (ESI+) calculated forC38H42N2O5S [ M + H ]+: 585.3362, found: 585.3356. White powder, yield: 56%, melting point: 105.9~107.3℃. 1 H NMR (400 MHz, Chloroform- d ) δ 8.58 – 8.49 (m, 2H), 7.25 (d, J = 5.5Hz, 2H), 6.44 (dd, J = 17.4, 11.0 Hz, 1H), 5.72 (d, J = 8.4 Hz, 1H), 5.32 – 5.12(m, 2H), 3.80 (s, 2H), 3.36 (d, J = 6.4 Hz, 1H), 3.13 (s, 2H), 2.88 – 2.76 (m,4H), 2.32 (p, J = 7.0 Hz, 1H), 2.23 – 2.13 (m, 2H), 2.07 (dq, J = 16.0, 8.5, 7.6Hz, 3H), 1.79 – 1.71 (m, 1H), 1.67 – 1.57 (m, 2H), 1.55 – 1.50 (m, 1H), 1.43(s, 4H), 1.38 – 1.21 (m, 3H), 1.15 (s, 4H), 0.87 (d, J = 7.0 Hz, 3H), 0.71 (d, J = 6.9 Hz, 3H). 13 C NMR (101 MHz, Chloroform- d ) δ 216.81, 168.55, 149.46, 148.99,148.98, 138.91, 122.63, 116.75, 74.23, 69.28, 69.13, 57.88, 51.78, 47.12,45.15, HRMS (ESI+) calculated forC 30 H 44 N₂O₄S [M + H] +: 529.3100, found: 529.3103. White powder, yield: 59%, melting point: 99.6~100.8℃. 1 H NMR (400 MHz, Chloroform- d ) δ 7.97 (s, 1H), 7.20 (d, J = 8.2 Hz, 2H), 6.61 (d, J = 6.9 Hz, 2H), 6.40 (dd, J = 17.4, 11.0 Hz, 1H), 5.67 (d, J = 8.4 Hz,1H), 5.33 – 5.13 (m, 2H), 3.94 – 3.78 (m, 2H), 3.33 (d, J = 6.4 Hz, 1H), 3.08(s, 2H), 2.31 – 2.25 (m, 1H), 2.23 – 2.11 (m, 2H), 2.06 (d, J = 3.0 Hz, 1H), 2.02 – 1.99 (m, 1H), 1.95 (s, 4H), 1.73 (dd, J = 14.3, 3.1 Hz, 1H), 1.66 – 1.53(m, 3H), 1.52 – 1.44 (m, 1H), 1.44 – 1.36 (m, 5H), 1.35 – 1.19 (m, 7H), 1.17– 1.03 (m, 5H), 0.85 (d, J = 7.0 Hz, 3H), 0.83 – 0.79 (m, 1H), 0.66 (d, J = 6.9Hz, 3H).

[0024] White powder, yield: 61%, melting point: 100.1~102.9℃. 1 H NMR (400 MHz, Chloroform- d ) δ 7.12 (d, J = 8.1 Hz, 2H), 6.68 (d, J = 8.1Hz, 2H), 6.46 (dd, J= 17.4, 11.0 Hz, 1H), 5.73 (d, J = 8.4 Hz, 1H), 5.25 (dd, J =51.7, 14.2 Hz, 2H), 3.71 (s, 2H), 3.36 (d, J = 6.5 Hz, 1H), 3.12 (s, 2H), 2.91– 2.75 (m, 4H), 2.32 (q, J = 6.3, 5.8 Hz, 1H), 2.28 – 2.16 (m, 2H), 2.07 (d, J =20.1 Hz, 2H), 1.81 – 1.71 (m, 1H), 1.70 – 1.58 (m, 2H), 1.57 – 1.49 (m, 1H), 1.44 (s, 4H), 1.31 (q, J = 18.3, 17.7 Hz, 3H), 1.16 (s, 3H), 1.10 (dd, J = 13.7, 4.4 Hz, 1H), 0.87 (t, J = 7.5 Hz, 4H), 0.71 (d, J = 6.9 Hz, 3H). 13 C NMR (101 MHz, Chloroform- d ) δ 217.78, 169.61, 156.32, 139.46, 130.48, 130.24, 117.81, 116.19,75.11, 70.02, 58.66, 53.23, 47.30, 45.94, 45.27, HRMS(ESI+) calculated for C 31 H 45 NO5S [M + H] + : 544.3097, found: 544.3090. White powder, yield: 56%, melting point: 102.8-104.6℃. 1 H NMR (400 MHz, DMSO-d 6) δ 7.26 – 7.21 (m, 4H), 6.88 – 6.84 (m, 4H), 6.13 (dd, J = 17.6, 11.2 Hz, 1H), 5.54 (d, J = 8.2 Hz, 1H), 5.10 – 5.01 (m,1H), 4.52 (d, J = 6.1 Hz, 1H), 3.72 (s, 6H), 3.43 (s, 3H), 3.18 – 3.08 (m, 2H), 2.74 (t, J = 7.1 Hz, 2H), 2.54 (d, J = 7.1 Hz, 7H), 2.40 (s, 1H), 2.19 (dd, J =19.1, 11.0 Hz, 1H), 2.08 (q, J = 9.3, 8.6 Hz, 3H), 1.62 (q, J = 13.5, 10.6 Hz,2H), 1.51 – 1.31 (m, 6H), 1.32 – 1.19 (m, 5H), 1.02 (s, 4H), 0.82 (d, J = 6.9Hz, 3H), 0.59 (d, J = 6.7 Hz, 3H). HRMS (ESI+) calculated for C 32 H 47 NO5S [ M + H] + :558.3253, found:558.3258. White powder, yield: 65%, melting point: 101.2-103.8℃. 1 H NMR (400 MHz, DMSO- d 6) δ 6.35 (d, J = 8.0 Hz, 2H), 6.28 (d, J = 7.9Hz, 2H), 5.26 (dd, J = 17.7, 11.1 Hz, 1H), 4.67 (d, J = 8.2 Hz, 1H), 4.23 – 4.10(m, 2H), 3.68 (d,J = 6.0 Hz, 1H), 2.79 (s, 1H), 2.60 (s, 1H), 2.39 – 2.23 (m,4H), 1.96 (ddd, J = 10.8, 8.5, 5.4 Hz, 1H), 1.82 (s, 3H), 1.62 (p, J = 1.9 Hz, 5H), 1.52 (s, 1H), 1.35 – 1.13 (m, 4H), 0.77 (t, J = 13.4 Hz, 2H), 0.49 – 0.41(m, 6H), 0.40 – 0.33 (m, 5H), 0.29 (dd, J = 6.9, 2.4 Hz, 7H), 0.15 (d, J = 19.1Hz, 4H), 0.07 (s, 3H), -0.06 (d, J = 6.9 Hz, 3H), -0.28 (dd, J = 13.4, 6.6 Hz, 3H). 13 C NMR (101 MHz, Chloroform- d ) δ 222.54, 222.52, 173.78, 147.02, 146.17, 133.12, 131.15, 131.09, 126.74, 126.68, 120.44, 74.65, 62.60, 52.95, 52.93, 52.84, 50.27, 49.30, 49.06, 46.75, 45.41, 45.20, 44.99, 44.78, 44.57, 44.36, 44.16, 41.70, 39.32, 38.91, 37.23, 37.13, 35.43, 33.86, 31.88, 29.79, 21.45,21.42, 19.90, 19.87, 19.83, 16.85. HRMS (ESI+) calculated for C 34 H 51 NO4S [M +H] + :570.3617, found:570.3617. White powder, yield: 67%, melting point: 95.3-96.6℃. 11H NMR (400 MHz, Chloroform- d ) δ 7.58 (d, J J = 7.7 Hz, 2H), 7.45 (d, J J = 7.9Hz, 1H), 6.47 (dd, J J = 17.1, 11.0 Hz, 1H), 5.74 (d, J J = 8.5 Hz, 1H), 5.43 – 5.06(m, 2H), 3.86 (s, 1H), 3.36 (s, 1H), 3.13 (d, J J = 9.7 Hz, 1H), 2.81 (dd, J J =14.0, 5.2 Hz, 2H), 2.39 – 2.14 (m, 3H), 2.07 (d, J J = 18.0 Hz, 2H), 1.77 (d, J J =15.2 Hz, 1H), 1.58 (d, J J = 42.2 Hz, 4H), 1.46 (q, J J = 9.7, 9.1 Hz, 4H), 1.41 –1.24 (m, 3H), 1.15 (d, J J = 7.9 Hz, 4H), 0.87 (dd, J J = 9.6, 5.8 Hz, 3H), 0.71 (dd, J J = 11.6, 6.8 Hz, 2H), 0.63 (d, J J = 7.2 Hz, 1H). HRMS (ESI+) calculated forC 32 H 44 F3NO4S [ M + H ] + :596.3021, found:596.3022. White powder, yield: 59%, melting point: 100.5 - 102.1 °C. 1 1H NMR (400 MHz, DMSO- d 6) δ 7.26 (dd, J J = 4.9, 2.9 Hz, 1H), 7.08 (dd, J J = 2.9,1.3 Hz, 1H), 6.87 (dd,J = 5.0, 1.3 Hz, 1H), 5.97 (dd, J = 17.7, 11.2 Hz, 1H), 5.37 (d, J = 8.2 Hz, 1H), 4.95 – 4.83 (m, 2H), 4.35 (d, J = 6.0 Hz, 1H), 3.51 (s,2H), 3.25 (d, J = 11.4 Hz, 1H), 3.12 – 2.98 (m, 3H), 2.22 (s, 1H), 2.06 – 1.85(m, 4H), 1.54 – 1.39 (m, 2H), 1.35 – 1.27 (m, 1H), 1.19 (s, 4H), 1.15 – 1.03(m, 3H), 0.88 (s, 4H), 0.64 (d, J = 6.9 Hz, 3H), 0.45 (d, J = 6.7 Hz, 3H). 13 C NMR (101 MHz, Chloroform- d ) δ 217.15, 169.74, 139.15, 127.73, 126.44, 123.00,117.47, 74.74, 69.98, 58.28, 48.06, 47.22, 45.58, 44.89, 44.09, 41.91, 36.85,36.16, 34.58, 34.53, 32.46, 30.54, 26.98, 26.50, 24.97, 17.02, 15.01, 11.66.HRMS (ESI+) calculated for C 29 H 43 NO4S2[M+H] + :534.2712, found:534.2716. White powder, yield: 62%, melting point: 100.9~102.8℃. 1 H NMR (400 MHz, Chloroform- d ) δ 7.30 – 7.26 (m, 2H), 7.03 – 6.97 (m,2H), 6.46 (dd, J= 17.4, 11.0 Hz, 1H), 5.73 (d, J = 8.5 Hz, 1H), 5.37 – 5.13 (m,2H), 3.76 (s, 2H), 3.35 (d, J = 6.5 Hz, 1H), 3.13 (s, 2H), 2.85 – 2.73 (m, 4H), 2.32 (q, J = 6.6 Hz, 1H), 2.26 – 2.14 (m, 2H), 2.11 – 2.02 (m, 2H), 1.69 – 1.49(m, 4H), 1.44 (s, 4H), 1.35 – 1.23 (m, 3H), 1.16 (s, 4H), 0.88 (d, J = 7.0 Hz, 4H), 0.72 (d, J = 7.0 Hz, 3H). HRMS (ESI+) calculated for C 31 H 44 FO4S [ M + H ] + :546.3053, found:546.3052. White powder, yield: 59%, melting point: 100.20~102.50℃. 1 H NMR (400 MHz, Chloroform- d ) δ 8.58 – 8.53 (m, 1H), 7.64 (td, J = 7.7, 1.8 Hz, 1H), 7.30 (d, J = 7.8 Hz, 1H), 7.15 (dd, J = 7.6, 4.9 Hz, 1H), 6.47 (dd, J = 17.4, 11.0 Hz, 1H), 5.73 (d, J = 8.4 Hz, 1H), 5.39 – 5.13 (m, 2H), 3.92 (s,2H), 3.35 (s, 1H), 3.15 (s, 2H), 2.90 – 2.76 (m, 4H), 2.33 (q, J= 7.1 Hz, 1H),2.27 – 2.16 (m, 2H), 2.13 – 2.04 (m, 2H), 1.80 – 1.72 (m, 1H), 1.65 (dt, J =16.4, 10.3 Hz, 2H), 1.58 – 1.50 (m, 1H), 1.44 (s, 5H), 1.34 (t, J = 14.8 Hz,2H), 1.16 (s, 4H), 0.87 (d, J = 7.0 Hz, 3H), 0.72 (d, J = 6.9 Hz, 3H). HRMS (ESI+) calculated for C 30 H 44 N₂O₄S [M + H] + :529.3100, found:529.3099. White powder, yield: 56%, melting point: 100.3-101.6℃. ¹H NMR (400 MHz, Chloroform- d ) δ 8.59 – 8.43 (m, 2H), 7.69 (dt, J = 7.7, 2.1Hz, 1H), 6.45 (dd, J = 17.4, 11.0 Hz, 1H), 5.73 (d, J = 8.4 Hz, 1H), 5.33 – 5.15(m, 2H), 3.81 (s, 2H), 3.38 (d, J = 6.4 Hz, 1H), 3.14 (s, 2H), 2.90 – 2.74 (m,4H), 2.35 (q, J = 6.9 Hz, 1H), 2.25 – 2.02 (m, 6H), 1.82 – 1.73 (m, 1H), 1.72 –1.53 (m, 3H), 1.48 – 1.40 (m, 4H), 1.39 – 1.22 (m, 3H), 1.16 (s, 4H), 0.90(d, J = 7.0 Hz, 3H), 0.72 (d, J = 6.9 Hz, 3H). 13C NMR (101 MHz, Chloroform- d ) δ 217.04, 168.70, 149.93, 149.39, 148.29, 139.18, 135.80, 135.32, 123.67,123.37, 123.10, 122.85, 116.81, 77.36, 74.36, 69.33, 58.07, 50.52, 47.21,45.33, 44.73, 43.84, 41.63, 36.61, 35.93, 34.35, 33.96, 32.64, 30.27, 26.71,26.59, 24.72, 16.69, 14.78, 11.44. HRMS (ESI+) calculated for C 30 H 44 N2O4S [ M +H ] + :529.3100, found:529.3095. White powder, yield: 59%, melting point: 98.90~100.50℃. 1H NMR (400 MHz, Chloroform-d) δ 7.17 (dd, J = 4.9, 1.4 Hz, 1H), 6.94 –6.86 (m, 2H), 6.44 (dd, J = 17.3, 11.0 Hz, 1H), 5.71 (d, J = 8.4 Hz, 1H), 5.34 – 5.11 (m, 2H), 3.97 (s, 1H), 3.39 – 3.25 (m, 1H), 3.11 (s, 2H), 2.87 –2.69 (m, 4H), 2.30 (h, J = 8.8, 7.8 Hz, 1H), 2.26 – 2.11 (m, 2H), 2.05 (dd, J= 18.1, 5.8 Hz, 2H), 1.75 (dt, J = 14.4, 3.0 Hz, 2H), 1.68 – 1.48 (m, 4H), 1.47 – 1.22 (m, 8H), 1.14 (s, 3H), 1.08 (dd, J = 13.8, 4.3 Hz, 1H), 0.86 (d,J = 6.9 Hz, 3H), 0.69 (p, J = 5.3, 4.5 Hz, 3H). 13C NMR (101 MHz, Chloroform-d) δ 217.16, 168.93, 168.84, 143.71, 139.14, 126.71, 125.09, 124.57, 117.23,74.62, 69.36, 69.32, 58.22, 47.88, 46.95, 45.49, 44.85, 43.96, 41.79, 36.80,36.73, 36.04, 34.50, HRMS (ESI+) calculated forC29H43NO4S2 [ M + H ]+:534.2712, found:534.2716. White powder, yield: 65%, melting point: 102.4~104.2℃. 1H NMR (400 MHz, Chloroform-d) δ 9.12 (s, 1H), 8.72 (s, 2H), 6.47 (dd, J =17.4, 11.0 Hz, 1H), 5.74 (d, J = 8.5 Hz, 1H), 5.34 – 5.15 (m, 2H), 3.82 (s,2H), 3.36 (s, 1H), 3.15 (s, 2H), 2.84 (dd, J = 6.6, 4.5 Hz, 2H), 2.82 – 2.76(m, 2H), 2.33 (p, J = 6.9 Hz, 1H), 2.20 (dq, J = 19.4, 8.8 Hz, 2H), 2.12 –1.99 (m, 2H), 1.80 – 1.61 (m, 5H), 1.61 – 1.51 (m, 1H), 1.50 – 1.40 (m, 5H), 1.40 – 1.27 (m, 2H), 1.16 (s, 4H), 0.88 (d, J = 7.0 Hz, 3H), 0.72 (d, J = 7.0Hz, 3H). HRMS (ESI+) calculated for C29H43N3O4S [ M + H ]+:530.3053, found:530.3051. White powder, yield: 58%, melting point: 99.8~100.6℃. 1H NMR (400 MHz, Chloroform-d) δ 7.38 (d, J = 1.9 Hz, 2H), 6.47 (dd, J =17.4, 11.0 Hz, 1H), 6.32 (dd, J = 3.2, 1.9 Hz, 2H), 6.22 (d, J = 3.2 Hz, 2H), 5.74 (d, J = 8.5 Hz, 1H), 5.36 – 5.09 (m, 2H), 3.68 (s, 4H), 3.35 (dd, J =10.6, 6.5 Hz, 1H), 3.14 (s, 2H), 2.72 (ddt, J = 11.5, 7.6, 3.5 Hz, 4H), 2.33(q, J = 7.9, 7.4 Hz, 1H), 2.28 – 2.14 (m, 2H), 2.12 – 1.99 (m, 2H), 1.76 (dd,J = 14.6, 3.1 Hz, 1H), 1.69 – 1.60 (m, 2H), 1.58 – 1.51 (m, 1H), 1.47 – 1.41(m, 5H), 1.39 – 1.23 (m, 3H), 1.15 (s, 4H), 0.87 (d, J = 7.0 Hz, 3H), 0.73(d, J = 6.9 Hz, 3H). 13C NMR (101 MHz, Chloroform-d) δ 216.91, 168.80,151.67, 141.94, 138.82, 109.99, 109.88, 108.79, 74.43, 68.93, 58.02, 52.10,49.42, 45.26, 43.71, 41.56, 35.80, 34.27, 34.11, 29.97, 26.14, 16.65, 11.32.HRMS (ESI+) calculated for C29H43NO5S [ M + H ]+:518.2940, found:518.2943.

[0025] 2. Study on the antibacterial activity of truncated pleurotin derivatives 2.1 In vitro antibacterial test Method for determining minimum inhibitory concentration: The microbroth dilution method is simple to perform and yields highly reliable results, making it one of the commonly used methods for evaluating the antibacterial activity of drugs. This method was used to evaluate the minimum inhibitory concentration (MIC) of compounds against susceptible Gram-positive and Gram-negative bacteria. The susceptible bacteria tested included: Gram-positive Staphylococcus aureus (…). S.aureus ATCC29223), Micrococcus luteus ( M.luteus CPCC10045) and Enterococcus faecalis ( E.faecalis ATCC29213), Gram-negative Escherichia coli ( E. coli ATCC25922) and Salmonella ( Salmonella (CICC 21513). Linezolid, meropenem, and levofloxacin, all commercially available drugs, were selected as quality control drugs, while tiamulin, vornimulin, retamorin, and lefamorin, all commercially available drugs that truncate pleurotin, were selected as control drugs.

[0026] Preparation of target compound stock solution Preparation of test solution: Accurately weigh 1.28 mg of the test drug (compounds 4-1 to 4-19 prepared in Examples 1 to 19 and the control drug), add 500 μL of DMSO, shake well to dissolve completely, and obtain a stock solution with a concentration of 2.56 mg / mL. Then take 100 μL of the 2.56 mg / mL stock solution and dilute it in 3.9 mL of MHB medium. Pipe and stir several times to make it uniform, and obtain a drug solution with a concentration of 64 μg / mL.

[0027] Preparation of the test bacterial suspension: The bacterial suspension stored at -80℃ was activated by streaking a single colony onto MHA medium using a looper in a biosafety cabinet using the crisscross method. The medium was then incubated at 37°C. After incubation, the activated single colony was inoculated into an EP tube containing 4 mL of MHB medium. Bacteria were collected by shaking the tube up and down, and then incubated at 37°C with a shaking incubator at 180 rap / min. The tube was observed to show turbidity during bacterial growth. Then, 200 μL of the bacterial suspension was added to 20 mL of MHB medium, yielding approximately 10⁻⁶ bacteria. 6 CFU / mL bacterial suspension.

[0028] The bacterial inoculum size is 1*10 5The minimum inhibitory concentration (MIC) of each antimicrobial agent against susceptible strains was determined using CFU / mL. A sterile 96-well plate was used. 200 μL of antimicrobial agent was added to the first well. 100 μL of MHB broth was added to wells 2-10 respectively. 100 μL of the antimicrobial agent was added to well 2 from well 1, mixed, and then 100 μL was added to well 3, and so on, until 100 μL was discarded from well 10. The drug concentrations in each well were then: 64, 32, 16, 8, 4, 2, 1, 0.5, 0.25, and 0.125 μg / mL, respectively. 200 μL of bacterial culture was added to well 11 as a positive control, and 200 μL of MHB broth was added to well 12 as a negative control. Then, 100 μL of the previously prepared bacterial culture was added to each of wells 1-10 to bring the final bacterial concentration in each tube to approximately 5 × 10⁻⁶. 5 The concentration of CFU / mL was doubled in each well. The inoculated 96-well plates were then incubated at 37°C for 18 hours. Bacterial growth was observed. The MIC value represents the lowest concentration at which the drug completely inhibits bacterial growth. Clear, transparent wells indicate that the drug inhibits bacterial growth at that concentration, while turbid wells indicate that the drug does not inhibit bacterial growth at that concentration. The clear, transparent wells at the lowest concentration represent the MIC value of the compound. The experiment was repeated three times.

[0029] Table 1. Antibacterial activity of compounds 4-1 to 4-19

[0030] As shown in Table 1, these truncated pleurotin derivatives exhibit good antibacterial activity against Gram-positive bacteria. Compounds 4-5, 4-7, 4-13, 4-16, and 4-17 show particularly good antibacterial activity against Gram-positive bacteria. S.aureus and E.faecalis It exhibits good antibacterial effects, superior to the control drugs tiamulin, vornimulin, retamorin, and lefamorin; among them, 4-7 pairs of truncated pleurotin derivatives are present. S.aureus Its MIC value is 64 times that of tiamulin, and it is effective against... M.luteus The MIC value is 32 times that of tiamulin, and it is effective against... E. coli Its MIC value is 8 times that of tiamulin; 4-13 pairs of truncated pleurotin derivatives S.aureus and E. coli The MIC values ​​were 32 times and 16 times that of tiamulin; 4-5 pairs Salmonella It has the best antibacterial effect, with a MIC value 8 times that of tiamulin.

[0031] The above description is only a preferred embodiment of the present invention and is not intended to limit the present invention. Any modifications, equivalent substitutions, and improvements made within the spirit and principles of the present invention should be included within the protection scope of the present invention.

Claims

1. A truncated pleurotin derivative compound, characterized in that, The general structural formula of the compound is shown in formula (1) below: 。 2. The truncated pleurotin derivative compound as described in claim 1, characterized in that, Selected from the following compounds: 。 3. The method for synthesizing the truncated pleurotin derivative compound as described in claim 1, characterized in that, The reaction route is as follows: 。 4. The method for synthesizing the truncated pleurotin derivative as described in claim 3, characterized in that, Includes the following steps: (1) Synthesis of intermediate 2: Weigh out the truncated pleurotin, add it to acetonitrile until completely dissolved, add p-toluenesulfonyl chloride, triethylamine, and sodium hydroxide while stirring, heat to reflux, extract, dry to obtain organic phase; continue to concentrate the organic phase under reduced pressure, purify by column chromatography to obtain intermediate 2; (2) Synthesis of intermediate 3: Intermediate 2 was added to an organic solvent, followed by mercaptoethylamine and DBU. The mixture was stirred in an ice bath. The pH was adjusted to 7-8 and the mixture was concentrated under reduced pressure. After extraction and drying, the organic phase was obtained. The organic phase was further concentrated under reduced pressure and purified by column chromatography to obtain intermediate 3. (3) Synthesis of target compound Intermediate 3 and an aldehyde compound containing the linking group R were stirred in a solvent until completely dissolved. Formic acid solution and anhydrous magnesium sulfate were added, and the reaction was carried out at room temperature. Sodium cyanoborohydride was added in batches, and the reaction was carried out at room temperature again. After the reaction was completed, the solvent was concentrated under reduced pressure and evaporated to dryness. The solution was extracted, dried, and the crude product was subjected to column chromatography and freeze-dried to obtain the target compound.

5. The use of the truncated pleurotin derivative compound as described in claim 1 or 2 in pharmaceutical preparation, characterized in that, It is used as an active ingredient in the preparation of antibacterial drugs.

6. The application of the truncated pleurotin derivative according to claim 5 in drug preparation, characterized in that, The bacteria susceptible to the aforementioned antimicrobial drugs include: Gram-positive Staphylococcus aureus (… S.aureus ATCC29223), Micrococcus luteus ( M. luteus CPCC10045) and Enterococcus faecalis ( E.faecalis ATCC29213), Gram-negative Escherichia coli ( E. coli ATCC25922) and Salmonella ( Salmonella CICC 21513).

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