In vitro and in vivo evaluation of novel ursolic acid derivatives as potential antibacterial agents against methicillin-resistant Staphylococcus aureus (MRSA)

Ying Sun; Xiaofang Li; Yan Wang; Xiangcun Shang; Wenhuan Huang; Song Ang; Dongli Li; Wing-Leung Wong; Weiqian David Hong; Kun Zhang; Panpan Wu

doi:10.1016/j.bioorg.2024.107986

In vitro and in vivo evaluation of novel ursolic acid derivatives as potential antibacterial agents against methicillin-resistant Staphylococcus aureus (MRSA)

Bioorg Chem. 2024 Nov 22:154:107986. doi: 10.1016/j.bioorg.2024.107986. Online ahead of print.

Authors

Affiliations

¹ School of Pharmacy and Food Engineering, Guangdong Provincial Key Laboratory of Large Animal Models for Biomedicine, Wuyi University, Jiangmen 529020, PR China.
² The State Key Laboratory of Chemical Biology and Drug Discovery, Department of Applied Biology and Chemical Technology, The Hong Kong Polytechnic University, Hung Hom, Kowloon, Hong Kong, China.
³ Department of Chemistry, University of Liverpool, Liverpool L69 7ZD, UK.
⁴ School of Pharmacy and Food Engineering, Guangdong Provincial Key Laboratory of Large Animal Models for Biomedicine, Wuyi University, Jiangmen 529020, PR China. Electronic address: kzhang@gdut.edu.cn.
⁵ School of Pharmacy and Food Engineering, Guangdong Provincial Key Laboratory of Large Animal Models for Biomedicine, Wuyi University, Jiangmen 529020, PR China. Electronic address: wyuchemwpp@wyu.edu.cn.

PMID: 39615282
DOI: 10.1016/j.bioorg.2024.107986

Abstract

The misuse and abuse of antibiotics have led to the increase of drug resistance and the emergence of multi-drug resistant bacteria. Therefore, it is an urgent need to develop novel antimicrobial agents to address this problem. Natural products (NPs) could provide an effective strategy for the discovery of drug due to their wide range of source and biological activities. Ursolic acid (UA) is a naturally occurring compound known for its wide range of biological properties. In this study, a series of UA derivatives were rationally designed and synthesized by incorporating antibacterial potential fragments of benzenesulfonamide and indole, with the aim of obtaining novel UA derivatives for the treatment of bacterial infections. Based on the preliminary screening, UA derivatives 27 (yield of 26 %), containing 4-chlorobenzenesulfonamide and 6-carboxyindole pharmacophores, as well as 34 (yield of 42 %), containing 4-carboxybenzenesulfonamide and unsubstituted indole pharmacophores, were identified as promising antibacterial agents against Staphylococcus aureus, especially for methicillin-resistant Staphylococcus aureus (MRSA), possessing MICs of 1 μM. Furthermore, both of them also displayed low hemolytic activity, non-resistance, and low-toxicity to mammalian cells. In addition, further mechanistic studies revealed that 27 and 34 were able to inhibit and eliminate MRSA biofilm formation, affecting the permeability of bacterial cell membrane, leading to increase intracellular reactive oxygen species (ROS) and ultimately inducing bacterial death. Notably, 27 and 34 also showed promising in vivo efficacy against MRSA in a mouse wound model. These results suggested that 27 and 34 should have promising applications against MRSA infection.

Keywords: Anti-MRSA; Derivatives; Design and synthesis; Mechanism; Ursolic acid.