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  3. Oleanolic acid derivatives against drug-resistant bacteria and fungi by multi-targets to avoid drug resistance

Oleanolic acid derivatives against drug-resistant bacteria and fungi by multi-targets to avoid drug resistance

  • Eur J Med Chem. 2024 Oct 5:280:116940. doi: 10.1016/j.ejmech.2024.116940.
Mei-Zhen Wei 1,  Zhao-Jie Wang 1,  Yan-Yan Zhu 1,  Wen-Biao Zu 1,  Yun-Li Zhao 1,  Xiao-Dong Luo 2
Affiliations

Affiliations

  • 1 Yunnan Characteristic Plant Extraction Laboratory, Key Laboratory of Medicinal Chemistry for Natural Resource, Ministry of Education and Yunnan Province, School of Chemical Science and Technology, Yunnan University, Kunming, 650500, People's Republic of China.
  • 2 Yunnan Characteristic Plant Extraction Laboratory, Key Laboratory of Medicinal Chemistry for Natural Resource, Ministry of Education and Yunnan Province, School of Chemical Science and Technology, Yunnan University, Kunming, 650500, People's Republic of China; State Key Laboratory of Phytochemistry and Plant Resources in West China, Kunming Institute of Botany, Chinese Academy of Sciences, Kunming, 650201, People's Republic of China. Electronic address: xdluo@ynu.edu.cn.
PMID: 39388902 DOI: 10.1016/j.ejmech.2024.116940
Abstract

Mixed infections caused by drug-resistant bacteria and fungi pose a severe threat to human health, and multi-target drugs may provide an effective approach to combat drug-resistant pathogens. Therefore, this study aimed to investigate the efficacies of some oleanolic acid (OA) derivatives against multidrug-resistant (MDR) bacteria and fungi using in vitro and in vivo experiments. Novel amphiphilic OA derivatives were designed and optimised, in which compounds G1 and J1 exhibited effective antimicrobial activity (MICs = 1-2 μg/mL), high selectivity against MDR strains, rapid bactericidal activity, and good predictive pharmacokinetics. Mechanistically, both compounds prevented drug resistance by disrupting the Bacterial cell membrane, inserting into the DNA, and binding to DNA gyrase. Additionally, J1 reduced microbial count in a mouse MRSA skin Infection model and accelerated wound healing much better than vancomycin. Conclusively, this study presents a new class of potential drugs for resistant bacteria and fungi.

Keywords

DNA binding activity; Drug-resistance; Membrane disruption; Multi-targets; Oleanolic acid.

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