A cyclic ester peptide compound, Aglomycin A, and its applications

Abstract

This invention relates to a cyclic ester peptide compound, aglomycin A, and its applications. The molecular formula of the compound aglomycin A is: C 35 H 45 ClN8O8S, with a molecular weight of 772; its chemical structure is as follows: This invention also relates to the application of the cyclic ester peptide compound aglomycin A in anti-infection, especially in anti-drug-resistant microbial infections.

Description

Technical Field

[0001] This invention belongs to the field of biomedical technology, specifically relating to a cyclic ester peptide compound, aglomycin A, and its applications. Background Technology

[0002] Antimicrobial resistance (AMR) refers to the ability of bacteria to evolve and adapt to one or more antibiotics, rendering previously effective drugs ineffective in treating bacterial infections. Currently, approximately 1.2 million people die annually from direct infections with drug-resistant bacteria, and this number is projected to reach 10 million by 2050. [1,2] Therefore, antibiotic resistance poses a significant threat to human health, survival, and socio-economic development.

[0003] Developing new antibiotics is crucial to solving the problem of antibiotic resistance, but the pace of new antibiotic development has slowed significantly in the last two decades. According to a report by the Biotechnology Innovation Organization (BIO), over 82% of antibiotics were approved before 2000. [3] Given the increasingly serious situation of drug resistance, the development of new antibiotics is urgently needed.

[0004] Halides have wide applications in drug research due to their broad biological and chemical activity. The introduction of halogens can enhance the efficacy, stability, and bioavailability of drugs. [4] Currently marketed halogen-containing drugs have the following activities: treatment of bacterial infections, such as ciprofloxacin and levofloxacin; treatment of fungal infections, such as fluconazole and itraconazole; anticancer activity, such as fluorouracil; and antihypertensive activity, such as chlorthalidone.

[0005] Nature is a significant source of halides, accounting for approximately one-fifteenth of the natural product database (NPAtlas). Our research group previously developed a specific discovery strategy targeting halides and used this strategy for screening, finding halides from a strain of actinomycete *Streptomyces agglomeratus* that we had previously isolated from Tibet. [5]A potential chlorinated derivative was discovered, and its fermentation product also exhibited activity against vancomycin-resistant Enterococcus faecium (VRE). HPLC-MS analysis of its metabolites revealed that the target compound possessed typical monochlorinated isotope mass spectra, with an intensity ratio of approximately 3:1 between the m / z 773 and 775 peaks, suggesting that this compound might be the active product of this strain. Therefore, based on the HPLC analysis results, we targeted and isolated this compound, and identified it as a novel cyclic ester peptide compound using NMR, MS, and Marfey reaction, naming it aglomycin A. Further investigation was conducted into the anti-VRE activity of this compound.

[0006] Based on this, the present invention is proposed.

[0007] [References]

[0008] 1.Thompson,T.,The staggering death toll of drug-resistantbacteria.Nature 2022.https: / / www.nature.com / articles / d41586-022-00228-x.

[0009] 2. Antimicrobial Resistance, C., Global burden of bacterial antimicrobial resistance in 2019: a systematic analysis. Lancet 2022, 399(10325), 629-655.

[0010] 3.May,M.,How to fight antibiotic resistance.Nat Med 2023,29(7),1583-1586.

[0011] 4. Benedetto Tiz, D.; Bagnoli, L.; Rosati, O.; Marini, F.; Sancineto, L.; Santi, C., New Halogen-Containing Drugs Approved by FDA in 2021: An Overview on Their Syntheses and Pharmaceutical Use. Molecules 2022, 27(5).

[0012] 5. Luo Yajun, Sun Hongmin, He Ning, et al. Isolation and antibacterial activity of actinomycetes from root nodules and rhizosphere soil of Hippophae rhamnoides in Tibet [J]. Biotechnology Bulletin, 2021, 37(11):225-236. Summary of the Invention

[0013] This invention first relates to a cyclic ester peptide compound, aglomycin A, the molecular formula of which is: C 35 H 45 ClN8O8S has a molecular weight of 772; its chemical structure is shown in formula (1).

[0014]

[0015] The present invention also relates to a pharmaceutical composition comprising the compound aglomycin A, the pharmaceutical composition comprising: a therapeutically effective amount of the compound aglomycin A, and necessary pharmaceutical excipients.

[0016] Preferably, the pharmaceutical composition is used to treat diseases caused by bacterial infections. Preferably, the bacteria include, but are not limited to, Enterococcus faecalis, vancomycin-resistant Enterococcus faecalis, Staphylococcus aureus, and methicillin-resistant Staphylococcus aureus.

[0017] Furthermore, the pharmaceutical composition further comprises a second antibacterial active substance, preferably linezolid.

[0018] This invention also relates to the following applications of the compound aglomycin A:

[0019] (1) Preparation of antibacterial infection drugs, wherein the bacteria include, but are not limited to, Enterococcus faecalis, vancomycin-resistant Enterococcus faecalis, Staphylococcus aureus, and methicillin-resistant Staphylococcus aureus;

[0020] (2) Preparation of combination antibacterial infection drugs, preferably, the combination is the combination of the compound aglomycin A and linezolid; the bacteria include, but are not limited to, Enterococcus faecalis, vancomycin-resistant Enterococcus faecalis, Staphylococcus aureus, and methicillin-resistant Staphylococcus aureus.

[0021] The beneficial effects of this invention are as follows:

[0022] (1) A novel chlorinated cyclic ester peptide compound, aglomycin A, was obtained by liquid fermentation of Streptomyces agglomeratus using a variety of separation techniques; aglomycin A has a significant inhibitory effect on Gram-positive bacteria.

[0023] (2) Aglomycin A was first discovered to have strong antibacterial activity against drug-resistant and non-drug-resistant Enterococcus faecalis, and it also showed strong anti-vancomycin-resistant Enterococcus faecalis activity in the in vivo model experiment of the giant wax moth.

[0024] (3) It was found that when aglomycin A and linezolid were used in combination, they had strong antibacterial activity against drug-resistant and non-drug-resistant Enterococcus faecalis, and also showed strong anti-vancomycin-resistant Enterococcus faecalis activity in the in vivo model experiment of the giant wax moth.

[0025] The results of this study suggest that the cyclic ester peptide compound aglomycin A has good application prospects for antibacterial activity. Attached Figure Description

[0026] Figure 1 The chemical structure of Aglomycin A and its 1 H- 1 H COSY (Bold), HMBC (Arrow), and ROESY (Dotted Arrow) related signals.

[0027] Figure 2 HRMS spectrum of Aglomycin A.

[0028] Figure 3 Secondary mass spectrum of Aglomycin A plus sodium ion (m / z 795.2628).

[0029] Figure 4 The results of the Marfey reaction of the acid hydrolysis product of Aglomycin A with the standard amino acid (LN-MeVal).

[0030] Figure 5 Marfey reaction results of acid hydrolysis products of Aglomycin A with standard amino acids (L-HPDA).

[0031] Figure 6 The results of the Marfey reaction of the acid hydrolysis product of Aglomycin A with the standard amino acid (L-Pro).

[0032] Figure 7 Marfey reaction results of acid hydrolysis products of Aglomycin A with standard amino acids (L-Thr and L-allo-Thr).

[0033] Figure 8 The four possible isomers of Aglomycin A are: isomer 1a, isomer 1b, isomer 1c, and isomer 1d.

[0034] Figure 9The checkerboard method was used to determine the inhibitory effect of the combined application of aglomycin A and linezolid on vancomycin-resistant Enterococcus faecalis.

[0035] Figure 10 Results of the inhibitory activity of Aglomycin A and linezolid against Enterococcus faecalis.

[0036] Figure 11 Results of the combined application of Aglomycin A and linezolid to inhibit the activity of Enterococcus faecalis.

[0037] Figure 12 Results of antibacterial activity of Aglomycin A and linezolid in an in vivo model of Enterococcus faecalis-infected larvae of the giant wax moth (A: 2.5 mg / kg aglomycin A and 0.5 mg / kg linezolid; B: 1 mg / kg aglomycin A and 1 mg / kg linezolid). Detailed Implementation

[0038] Example 1: Scale-up fermentation of the strain and extraction and purification of the fermentation broth

[0039] 1. Fermentation of endophytic actinomycetes agglomeratus in lichens

[0040] Streptomyces agglomeratus was cultured on ISP2 solid medium at 28°C for 7 days, then transferred to ISP2 solid medium for another 7 days. Afterwards, approximately 1 cm... 2 Solid cultures of various sizes were inoculated into 50 mL of ISP2 liquid medium and cultured at 220 rpm and 28 °C for 48 hours to obtain seed culture.

[0041] Streptomyces agglomeratus was fermented on M3 medium. A total of 150 500 mL Erlenmeyer flasks were inoculated, with 5 mL of seed culture added to each flask. The flasks were cultured with shaking at 28°C for 9 days.

[0042] 2. Crude purification and concentration of fermentation broth

[0043] The fermentation broth (15 L) of the above strain was centrifuged at 8,000 rpm for 10 min, and the supernatant was collected. The supernatant was treated with D4006 macroporous adsorption resin (column volume 1.5 L). It was washed with 5 L of deionized water until nearly colorless, and then eluted successively with 50% ethanol-water, 70% ethanol-water, and 100% ethanol (5 L each). The eluents were concentrated under vacuum to obtain the following three fractions: Fr. A (50% ethanol fraction), Fr. B (70% ethanol fraction), and Fr. C (100% ethanol fraction).

[0044] 3. Preparation of the novel cyclic ester peptide compound aglomycin A

[0045] The above-mentioned Fr.C components were further separated by reversed-phase medium-pressure column chromatography (0 min-100 min, 25%-100% acetonitrile / water; 100.1 min-120 min, 100% acetonitrile, flow rate 5 mL / min). Based on the liquid chromatography-mass spectrometry results, similar components were combined into the following four parts: Fr.C1-Fr.C4.

[0046] Fr.C3 was semi-preparatively purified by Agilent 1200 HPLC (YMC-C8, 10 μm, 10 × 250 mm, 51% acetonitrile / water, 2.5 mL / min). The eluent was collected according to the retention time and concentrated and dried under reduced pressure to obtain the compound aglomycin A shown in Formula 1.

[0047] Example 2: Structural identification of the cyclic ester peptide compound aglomycin A

[0048] 1. Aglomycin A (compound 1) is a white powder, readily soluble in methanol;

[0049] High-resolution mass spectrometry (HS-MS) Figure 2 The quasi-molecular ion peak is shown to be 773.2849 m / z [M+H]. + (C 35 H 46 The theoretical calculated value of ClN8O8S is 773.2848 (with an error of 0.1 ppm), indicating that the molecular formula of compound 1 is C. 35 H 45 ClN8O8S has an unsaturation degree of 17. 1 H and 13 12C NMR (DMSO-d6, Table 1) data showed the presence of 6 amides (δ¹⁸ C NMR spectroscopy). C 159.2–170.4,δ H 6.78-8.26), 1 nitrogen-methyl group (δ H 3.07), the signal of 10 oxygen or nitrogen-substituted methines (δ C 46.6–70.3, δ H 2.51–5.22), 1 o-trisubstituted phenyl group [δ C 114.8–142.1,δ H 7.49, d(9.0); 6.73, t(9.0); 7.68, d(7.8)], 1 2,4-substituted thiazole (δ C 168.2, 148.7, 123.3; δ H 8.37,s). 1The H NMR spectrum shows two active protons (δ). H 7.30,s) indicates the presence of one primary amine.

[0050] The mass spectrometry signal of compound 1 [M+H] + The secondary mass spectrometry at m / z 773.2849 showed that the compound had imine ions at 70.066, 86.097 and 85.075, suggesting that the compound may contain proline (Pro), N-methylvaline (N-MeVal) and hexahydropyridazine-3-carboxylic acid (HPDA). 1 H- 1 1H COSY spectroscopy revealed that compound 1 has six spin systems. Figure 1 They are: CH / CH / CH, NH / CH / CH / CH3, CH / CH2 / CH2 / CH2, NH / CH2 / CH2 / CH2 / CH, NH / CH and CH / CH / CH3(CH3). Based on the HMBC spectrum, the correlation between H-2-Thr and NH-2-Thr and C-1-Thr indicates the presence of a serine (Thr) residue in the structure; the correlation between H-2-Pro and H2-3-Pro and C-1-Pro confirms the presence of a Pro residue; the correlation between H-2-HPDA and C-4-HPDA and C-1-HPDA, and between NH-5-HPDA and C-2-HPDA, further confirms the presence of an HPDA residue; the correlation between H-2-(N-MeVal) and C-1-(N-MeVal), and between N-CH3-(N-MeVal) and C-2-(N-MeVal), further confirms the presence of an N-MeVal residue in compound 1; the correlation between NH2-2′-ACTA and C-1′-ACTA, and between H-6′-ACTA and... The presence of 2-(2-amino-3-chlorophenyl)-4-thiazocarboxylic acid (ACTA) in the structure is inferred from the correlation between C-1′-ACTA, C-2′-ACTA, and C-2′-ACTA; H-4′-ACTA is correlated with C-3′-ACTA; and H-5-ACTA is correlated with C-2-(epoxy-Val) and C-3-(epoxy-Val). Furthermore, H-2-(epoxy-Val) is correlated with C-1-(epoxy-Val), C-3-(epoxy-Val), and C-5-(epoxy-Val); and H-4-(epoxy-Val) is correlated with C-2-(epoxy-Val) and C-3-(epoxy-Val). Based on the unsaturation of this compound, it is inferred that this fragment is a 3,4-epoxyvaline (epoxy-Val).

[0051] Information on secondary mass spectrometry fragments of sodium-added ions at m / z 795.2628 based on compound 1 ( Figure 3Furthermore, in HMBC, NH-2-Thr is associated with C-1″-ACTA, H-2-HPDA with C-1-Pro, H-2-(epoxy-Val) with C-1-HPDA, H-2-(N-MeVal) with C-1-(epoxy-Val), and H-3-Thr with C-1-(N-MeVal), thus determining that the above amino acid fragments are linked into a ring, with the linkage order being [-Thr(ACTA)-Pro-HPDA-(epoxy-Val)-(N-MeVal)-]. This confirms the planar structure of compound 1.

[0052] Table 1 Compound 1 1 H and 13 C NMR data

[0053]

[0054] Example 3: Confirmation of the stereoconfiguration of the cyclic ester peptide compound aglomycin A (compound 1)

[0055] 1. Confirmation of the relative configuration of Aglomycin A

[0056] The ROESY spectrum shows that H-2-Pro of compound 1 is correlated with H-2-HPDA, indicating that the peptide bond formed between Pro and HPDA is in the cis configuration; in addition, the Δδ in Pro... Cβ-Cγ The difference was 4.2 ppm, which led to the conclusion that the amide bond formed between Thr and Pro was in the trans configuration.

[0057] 2. Confirmation of the absolute configuration of Aglomycin A

[0058] (1) Absolute configuration of amino acid residues in the acid hydrolysis product of aglomycin A was confirmed by the advanced Marfey reaction.

[0059] Aglomycin A was acid-hydrolyzed under HCl conditions, followed by derivatization with L- and D-FDAA reagents, and then analyzed by LC-MS. Comparison with retention times of L-FDAA or D-FDAA-derived LN-Me-Val, L-HPDA, L-Thr, L-allo-Thr, and L-Pro standards confirmed that all amino acid residues in aglomycin A are in the L-configuration. Figure 4-7 ).

[0060] Acid hydrolysis of Aglomycin A and higher Marfey reactions

[0061] 0.5 mg of compound 1 was dissolved in 200 μL of 6N HCl, sealed, and acid-hydrolyzed at 110 °C for 16 h. The resulting hydrolysate was divided into two equal portions and dried under N2. One portion of the acid hydrolysate was added to 30 μL of 0.1 M NaHCO3 solution, followed by 30 μL of L-FDAA acetone solution, and reacted at 40 °C for 1 h. The reaction was terminated by adding 30 μL of 1 M HCl, and then diluted with 200 μL of acetonitrile. The preparation method of the D-FDAA derivative was the same.

[0062] Weigh 50 μg of standard amino acids, add 30 μL of 0.1 M NaHCO3 solution, and then add 30 μL of L-FDAA acetone solution. React at 40 °C for 1 h. After terminating the reaction with 30 μL of 1 M HCl, dilute with 200 μL of acetonitrile. The preparation method for D-FDAA derivatives is the same.

[0063] LC-MS Analysis Method: Instruments: ACQUITY UPLC Arc system; Detector: SQD2detector; Analysis column: Waters ACQUITY UPLC BEH C 18 Column (1.7μm, 100×2.1mm); Column temperature: 40℃; Mobile phase: Phase A: 1‰ formic acid-water, Phase B: 1‰ formic acid-acetonitrile; Isocratic elution: 0~13min, 70% A+30% B; Flow rate: 0.3mL / min.

[0064] (2) The absolute configuration of the 3,4-epoxy-Val residue in the acetal peptide compound aglomycin A was confirmed using quantum chemical calculations.

[0065] In addition to the absolute amino acid configurations already determined, compound 1 still has four possible diastereomers (compound 1a-compound 1d, ...). Figure 8 To simplify the calculation process without affecting the results, we replaced ACTA with acetic acid. Subsequently, we evaluated the four isomers using GIAO NMR calculations and the DP4+ method. The calculations yielded the results for compound 1a. 1 H and 13 The C chemical shift value is closer to the experimental value, and the CMAE value is the smallest in the DP4+ probability statistical analysis, with a probability of 99.99% (Table 2). Finally, the absolute configuration of the 3,4-epoxy-Val residue in 1 is determined to be 2S,3S (corresponding to...). Figure 8 (Structure of compound 1a).

[0066] Table 2.1a-1d shows the DP4+ probability calculation results.

[0067]

[0068] Quantum chemical calculations

[0069] Using Macromodel software with MMFF force fields, each conformation was searched using DMSO as solvent and a 100,000-step mixed torsional low-mode sampling algorithm was employed for conformational analysis, with a threshold of 40 kJ / mol. The obtained conformations were further optimized using semi-empirical quantum chemistry methods coupled with GFN2-xTB from the xTB package, and clustered using the molclus program. Conformations with relative energies less than 5 kcal / mol were retained and further optimized using Gaussian 16 software at the B3LYP / 6-31G theoretical level. NMR calculations were performed on conformations with relative energies below 2.5 kcal / mol at the PCM / mPW1PW91 / 6-311+G(d,p) level.

[0070] The unnormalized chemical shift (δu) is calculated using the function δu = σ0 - σx, where σx is the Boltzmann mean shielding tensor, and σ0 = 188.654 is the shielding constant for the carbon atom in tetramethylsilane (TMS) calculated at the same theoretical level as σx. The normalized chemical shift (δs) is calculated using the expression δs = (δu – b) / a, where a and b are obtained through linear regression δu = aδexp + b. The mean absolute error (MAE) is defined as ∑n|δu - δexp| / n. The corrected mean absolute error (CMAE) is defined as ∑n|δs - δexp| / n.

[0071] Example 5: Antibacterial activity of the cyclic ester peptide compound aglomycin A

[0072] 1. In vitro antibacterial activity of aglomycin A, a novel cyclic ester peptide compound

[0073] The antibacterial activity of aglomycin A against seven microorganisms—Enterococcus faecalis (ATCC 35667), Staphylococcus aureus (ATCC 29213), Escherichia coli (ATCC 25922), Klebsiella pneumoniae (ATCC BAA2470), Acinetobacter baumannii (ATCC 19606), Pseudomonas aeruginosa (ATCC 27853), and Candida albicans (ATCC 10231)—was evaluated using the microplate method (Table 3). The results showed that compound 1 exhibited good antibacterial activity against Enterococcus faecalis (ATCC 35667) and Staphylococcus aureus (ATCC 29213) (MIC = 4-8 μg / mL). Aglomycin A showed no activity against Gram-negative bacteria or fungi, indicating that this compound is a narrow-spectrum antibiotic targeting Gram-positive bacteria.

[0074] Table 3 Results of in vitro antibacterial activity of compound 1

[0075]

[0076]

[0077] Note: 1-7 are sensitive strains, and 8-13 are drug-resistant strains.

[0078] 2. Antibacterial activity of the novel cyclic ester peptide compound aglomycin A against clinically isolated microorganisms.

[0079] Based on the good performance of compound 1 against susceptible strains, its MIC against six different clinically isolated drug-resistant bacteria was further determined. Compound 1 significantly inhibited the growth of *Enterococcus faecalis* (VRE) carrying vancomycin resistance genes and methicillin-resistant Staphylococcus aureus (MRSA) (Table 3). Nine clinically isolated *Enterococcus faecalis* and *Enterococcus faecium* strains were selected, along with seven clinically used first- or second-line antibiotics as control groups to further identify the antibacterial activity of compound 1 (Table 4). The results showed that compound 1 had inhibitory effects on clinical isolates from different tissues, and maintained stable antibacterial activity against highly resistant strains of ampicillin, gentamicin, vancomycin, and daptomycin. In particular, it showed strong activity against vancomycin-resistant *Enterococcus faecalis*, regardless of whether the VanA or VanB genotype was present. Therefore, the antibacterial activity of compound 1 is not limited to susceptible strains, and its inhibitory effect on clinical isolates is comparable to that of most commonly used clinical antibiotics.

[0080] Table 4. Antibacterial activity of compound 1 against clinically isolated enterococci.

[0081]

[0082] 3. Assay of the synergistic antibacterial activity of aglomycin A (compound 1), a novel cyclic ester peptide compound.

[0083] For VRE-related infections, the range of clinically available antibacterial drugs is limited, and even fewer are available for VanA genotype VRE, primarily linezolid and dalfopristin / quinuprine. To explore the combined efficacy of compound 1 with clinically used anti-VRE drugs, the synergistic antibacterial activity of compound 1 with first-line antibiotics was tested. Based on the checkerboard method, compound 1 was combined with linezolid, dalfopristin, and quinuprine, respectively, and their antibacterial activity was evaluated after culturing for the same period. The results showed that compound 1 and linezolid exhibited synergistic antibacterial activity, with a FIC between 0.375 and 0.5, significantly reducing the required dosage of both. Figure 9 ).

[0084] 4. Evaluation of the antibacterial modality of a novel cyclic ester peptide compound, aglomycin A

[0085] In addition, we investigated the antibacterial mechanism of compound 1 and plotted its antibacterial curve against Enterococcus faecalis. Figure 10 Compared with the blank control group, compound 1 significantly inhibited the growth of Enterococcus faecalis. With increasing concentration, the inhibition time of bacteria gradually increased, but no matter how high the concentration, it failed to reduce the colony count in the culture medium to 0. According to the antibacterial curve, aglomycin A and the positive control group linezolid had similar effects, and their antibacterial mode was time-dependent inhibition.

[0086] Similarly, mixtures of compound 1 and linezolid at different concentrations were added to bacterial culture media, and the bacterial count in the culture media was monitored periodically using the same method to plot synergistic antibacterial curves. Figure 11 The synergistic combination showed significantly stronger inhibitory effects on bacteria than the single drug, and under the conditions of aglomycin A2×MIC + linezolid 0.5×MIC, it was able to reduce the colony count by 100-fold, to some extent transforming the two antibacterial compounds into antibiotics with bactericidal activity.

[0087] 5. In vivo antibacterial activity of the novel cyclic ester peptide compound aglomycin A

[0088] The in vivo antibacterial activity of compound 1 was evaluated using a *Enterococcus faecium* (ATCC 35667)-*G. mellonella* insect model infected with *Enterococcus faecium* (ATCC 35667). Figure 12As shown, the survival rate of larvae in the blank control group was only 30% 72 hours after infection. Aglomycin A and linezolid alone only provided some protection within 48 hours after infection, with the 72-hour survival rate being the same as the blank control group. However, the synergistic experimental groups of 2.5 mg / kg aglomycin A and 0.5 mg / kg linezolid, and 1 mg / kg aglomycin A and 1 mg / kg linezolid maintained survival rates of 90% and 70% respectively for up to 120 hours after infection, significantly higher than the single-drug groups. Therefore, the synergistic use of aglomycin A and linezolid can enhance the in vivo resistance to Enterococcus faecalis.

[0089] Finally, it should be noted that the above embodiments are only used to help those skilled in the art understand the essence of the present invention, and are not intended to limit the scope of protection of the present invention.

Claims

1. A cyclic ester peptide compound, aglomycin A, wherein the molecular formula of aglomycin A is: C 35 H 45 ClN8O8S has a molecular weight of 772; its chemical structure is shown in formula (1). Equation (1).

2. A drug comprising the cyclic ester peptide compound aglomycin A of claim 1.

3. The drug according to claim 2, characterized in that, The drug also contains a second antibacterial active substance; the second antibacterial active substance is linezolid.

4. The following applications of the cyclic ester peptide compound aglomycin A according to claim 1: (1) Preparation of antibacterial drugs; the bacteria are: Enterococcus faecalis, vancomycin-resistant Enterococcus faecalis, Staphylococcus aureus, and methicillin-resistant Staphylococcus aureus; (2) Preparation of combination antibacterial drugs; wherein the combination is the combination of the compound aglomycin A and linezolid; wherein the bacteria are: Enterococcus faecalis, vancomycin-resistant Enterococcus faecalis, Staphylococcus aureus, and methicillin-resistant Staphylococcus aureus.

Images