Discovery of urea-based pleuromutilin derivatives as potent gram-positive antibacterial agents

Zhenhua Wu; Xiaoli Zhu; Anjin Hong; Guanghui He; Zheng Wang; Qingyan Xu; Zhiyu Hu; Xiaobing Wu; Yuezhou Wang; Qiufang Chen; Xilin Zhao; Li Li; Xianming Deng

doi:10.1016/j.bioorg.2023.106547

Discovery of urea-based pleuromutilin derivatives as potent gram-positive antibacterial agents

Bioorg Chem. 2023 Jul:136:106547. doi: 10.1016/j.bioorg.2023.106547. Epub 2023 Apr 19.

Authors

Zhenhua Wu¹, Xiaoli Zhu¹, Anjin Hong¹, Guanghui He¹, Zheng Wang¹, Qingyan Xu¹, Zhiyu Hu¹, Xiaobing Wu¹, Yuezhou Wang¹, Qiufang Chen², Xilin Zhao³, Li Li⁴, Xianming Deng⁵

Affiliations

¹ State Key Laboratory of Cellular Stress Biology, School of Life Sciences, Faculty of Medicine and Life Sciences, Xiamen University, Xiamen, Fujian 361102, China; State-province Joint Engineering Laboratory of Targeted Drugs from Natural Products, Xiamen University, Xiamen, Fujian 361102, China.
² Women and Children's Hospital, School of Medicine, Faculty of Medicine and Life Sciences, Xiamen University, Xiamen, Fujian 361102, China.
³ State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, School of Public Health, Xiamen University, Xiamen, Fujian 361102, China.
⁴ State Key Laboratory of Cellular Stress Biology, School of Life Sciences, Faculty of Medicine and Life Sciences, Xiamen University, Xiamen, Fujian 361102, China; State-province Joint Engineering Laboratory of Targeted Drugs from Natural Products, Xiamen University, Xiamen, Fujian 361102, China. Electronic address: lli@xmu.edu.cn.
⁵ State Key Laboratory of Cellular Stress Biology, School of Life Sciences, Faculty of Medicine and Life Sciences, Xiamen University, Xiamen, Fujian 361102, China; State-province Joint Engineering Laboratory of Targeted Drugs from Natural Products, Xiamen University, Xiamen, Fujian 361102, China. Electronic address: xmdeng@xmu.edu.cn.

PMID: 37105000
DOI: 10.1016/j.bioorg.2023.106547

Abstract

There is an urgent need to discover new antibacterial drugs and provide new treatment options for clinical antimicrobial resistance (AMR) pathogen infections. Inspired by the structural insights from analyzing the co-crystal structure of lefamulin with the ribosomes of S. aureus, a series of novel pleuromutilin derivatives of phenylene sulfide incorporated with urea moiety were designed and synthesized. The structure-activity relationship (SAR) study revealed that derivatives with urea in the meta position of phenylene sulfide had optimal antibacterial activities in vitro. Among them, 21h was the most potent one against Methicillin-resistant Staphylococcus aureus (MRSA) and clinical AMR Gram-positive bacteria with minimum inhibitory concentrations (MICs) in the range of 0.00195-0.250 μg/mL. And it possessed low resistance frequency, prolonged Post-Antibiotic Effect and the capability to overcome lefamulin-induced resistance. Furthermore, 21h exhibited potent antibacterial activity in vivo in both the thigh infection model and trauma infection model, representing a promising lead for the development of new antibiotics against Gram-positive pathogens, especially for AMR bacteria.

Keywords: Antimicrobial resistance; Methicillin-resistant Staphylococcus aureus; Pleuromutilin; Urea-based pleuromutilin derivatives.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Anti-Bacterial Agents* / chemistry
Anti-Bacterial Agents* / pharmacology
Methicillin-Resistant Staphylococcus aureus*
Microbial Sensitivity Tests
Pleuromutilins
Staphylococcus aureus
Structure-Activity Relationship
Sulfides / pharmacology

Substances

Anti-Bacterial Agents
lefamulin
Sulfides