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

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.