Discovery, synthesis, and antibacterial activity of novel myrtucommulone analogs as inhibitors of DNA gyrase and topoisomerase IV

Hao Yang; Jian Li; Bo-Lin Wang; Xin-Ya Yang; Yu Zhang

doi:10.1016/j.ejmech.2024.117138

Discovery, synthesis, and antibacterial activity of novel myrtucommulone analogs as inhibitors of DNA gyrase and topoisomerase IV

Eur J Med Chem. 2025 Feb 5:283:117138. doi: 10.1016/j.ejmech.2024.117138. Epub 2024 Dec 8.

Authors

Hao Yang¹, Jian Li², Bo-Lin Wang², Xin-Ya Yang², Yu Zhang³

Affiliations

¹ School of Pharmacy, Ningxia Medical University, Yinchuan, 750004, China.
² School of Pharmaceutical Science, Hengyang Medical School, University of South China, Hengyang, 421001, China.
³ School of Pharmaceutical Science, Hengyang Medical School, University of South China, Hengyang, 421001, China. Electronic address: [email protected].

PMID: 39662286
DOI: 10.1016/j.ejmech.2024.117138

Abstract

Drug-resistant bacterial infections have emerged as a new challenge in anti-infective treatment, posing a significant threat to public health. DNA gyrase and topoisomerase IV (Topo IV) are promising targets for designing new antibiotics. Myrtus communis L. has long been used as a traditional herb for antisepsis and disinfection; however, the underlying mechanism of the antibacterial activity remains unclear. In this study, a class of novel myrtucommulone derivatives was synthesized and evaluated for DNA gyrase and Topo IV inhibitions. Analog 27 was the most potent DNA gyrase and Topo IV inhibitor. In bioactivity assays, molecule 27 exhibited a significant antibacterial effect against methicillin-resistant Staphylococcus aureus (MRSA). Additionally, it exhibited rapid bactericidal properties, low toxicity, and low inducing bacterial resistance. It demonstrated synergistic effects with ofloxacin, amikacin, cefepime, and ceftazidime, which make it a potential candidate for antimicrobial application. This work will facilitate the future development of myrtucommulone-based DNA gyrase and Topo IV inhibitors as novel antimicrobials to combat the increasing prevalence of multidrug-resistant bacteria.

Keywords: Antibacterial activity; DNA gyrase; DNA topoisomerase IV; Inhibitors; Myrtucommulone.

MeSH terms

Anti-Bacterial Agents* / chemical synthesis
Anti-Bacterial Agents* / chemistry
Anti-Bacterial Agents* / pharmacology
DNA Gyrase* / metabolism
DNA Topoisomerase IV* / antagonists & inhibitors
DNA Topoisomerase IV* / metabolism
Dose-Response Relationship, Drug
Drug Discovery
Humans
Methicillin-Resistant Staphylococcus aureus* / drug effects
Microbial Sensitivity Tests*
Molecular Structure
Structure-Activity Relationship
Topoisomerase II Inhibitors* / chemical synthesis
Topoisomerase II Inhibitors* / chemistry
Topoisomerase II Inhibitors* / pharmacology

Substances

Anti-Bacterial Agents
DNA Topoisomerase IV
DNA Gyrase
Topoisomerase II Inhibitors