Semisynthetic pleuromutilin antimicrobials with therapeutic potential against methicillin-resistant Staphylococcus aureus by targeting 50S ribosomal subunit

Xiao Wang; Rui Wang; Zhao-Sheng Zhang; Guang-Yu Zhang; Zhen Jin; Rong Shen; Dan Du; You-Zhi Tang

doi:10.1016/j.ejmech.2022.114341

Semisynthetic pleuromutilin antimicrobials with therapeutic potential against methicillin-resistant Staphylococcus aureus by targeting 50S ribosomal subunit

Eur J Med Chem. 2022 Jul 5:237:114341. doi: 10.1016/j.ejmech.2022.114341. Epub 2022 Apr 12.

Authors

Xiao Wang¹, Rui Wang², Zhao-Sheng Zhang³, Guang-Yu Zhang³, Zhen Jin⁴, Rong Shen⁵, Dan Du⁶, You-Zhi Tang⁷

Affiliations

¹ Guangdong Provincial Key Laboratory of Veterinary Pharmaceutics Development and Safety Evaluation, College of Veterinary Medicine, South China Agricultural University, Guangzhou, 510642, China; Cancer Research Center, Department of Stomatology, School of Medicine, Xiamen University, Xiamen, Fujian, China; Guangdong Laboratory for Lingnan Modern Agriculture, Guangzhou, 510642, China.
² Cancer Research Center, Department of Stomatology, School of Medicine, Xiamen University, Xiamen, Fujian, China; Fujian Provincial Key Laboratory of Reproductive Health Research, School of Medicine, Xiamen University, Xiamen, Fujian, China.
³ Guangdong Provincial Key Laboratory of Veterinary Pharmaceutics Development and Safety Evaluation, College of Veterinary Medicine, South China Agricultural University, Guangzhou, 510642, China.
⁴ Guangdong Provincial Key Laboratory of Veterinary Pharmaceutics Development and Safety Evaluation, College of Veterinary Medicine, South China Agricultural University, Guangzhou, 510642, China; Guangdong Laboratory for Lingnan Modern Agriculture, Guangzhou, 510642, China.
⁵ Cancer Research Center, Department of Stomatology, School of Medicine, Xiamen University, Xiamen, Fujian, China.
⁶ Cancer Research Center, Department of Stomatology, School of Medicine, Xiamen University, Xiamen, Fujian, China; Fujian Provincial Key Laboratory of Reproductive Health Research, School of Medicine, Xiamen University, Xiamen, Fujian, China. Electronic address: dandu@xmu.edu.cn.
⁷ Guangdong Provincial Key Laboratory of Veterinary Pharmaceutics Development and Safety Evaluation, College of Veterinary Medicine, South China Agricultural University, Guangzhou, 510642, China; Guangdong Laboratory for Lingnan Modern Agriculture, Guangzhou, 510642, China. Electronic address: youzhitang@scau.edu.cn.

PMID: 35430480
DOI: 10.1016/j.ejmech.2022.114341

Abstract

A series of pleuromutilin analogs with a substituted 1,2,4-triazole were designed, synthesized and assessed for their in vitro and in vivo antibacterial activity. Initially, the MIC of the synthesized derivatives against five strains of Staphylococcus aureus (MRSA ATCC 43300, S. aureus ATCC 29213, clinical isolation of S. aureus AD3, S. aureus 144 and S. aureus SA17) were tested by the broth dilution method. Compounds 30a, 31b and 32a were the most active antibacterial agents in vitro against MRSA (MIC = 0.0625 μg/mL). The results of the time-kill curves showed that compounds 30a and 32a could reduce the amount of MRSA in vitro quickly (-7.70 log₁₀ CFU/mL and -7.10 log₁₀ CFU/mL reduction). In the experiment to further evaluate the in vivo antibacterial activity of compound 30a against MRSA, compound 30a (-1.71 log10 CFU/g) was effective in reducing MRSA load in thigh infected mice. Compound 30a (survival rate was 50%) displayed superior in vivo efficacy to that of tiamulin (survival rate was 30%) in the mouse systemic model. The results of further pharmacokinetic studies on compound 30a showed that the half-life (t_1/2), clearance rate (Cl) and the area under the plasma concentration time curve (AUC_0→∞) of compound 30a were 0.37 h, 5.43 L/h/kg and 1.84 μg h/mL, respectively. After affinity measurement by surface plasmon resonance (SPR), compound 30a exhibited high affinity with the 50S ribosome, with K_D value of 1.95 × 10^-6 M. Furthermore, the results of molecular docking studies revealed that compound 30a was successfully localized inside the binding pocket of 50S ribosomal subunit (ΔG_b = -9.40 kcal/mol). Meanwhile, most of these compounds had no significant inhibitory effect on RAW 264.7 cells and 16HBE cells at the concentration of 8 μg/mL. The obtained outcomes showed that compound 30a could be utilized as an encouraging perspective in the development of a new therapeutic candidate for bacterial infection.

Keywords: 50S ribosome; MRSA; Molecular docking; Pleuromutilin; SPR.

MeSH terms

Animals
Anti-Bacterial Agents / chemistry
Diterpenes
Drug Design
Methicillin-Resistant Staphylococcus aureus*
Mice
Microbial Sensitivity Tests
Molecular Docking Simulation
Pleuromutilins
Polycyclic Compounds
Ribosome Subunits
Staphylococcus aureus

Substances

Anti-Bacterial Agents
Diterpenes
Polycyclic Compounds