Yang Hao, Li Jian, Wang Bo-Lin, Yang Xin-Ya, Zhang Yu
School of Pharmacy, Ningxia Medical University, Yinchuan, 750004, China.
School of Pharmaceutical Science, Hengyang Medical School, University of South China, Hengyang, 421001, China.
Eur J Med Chem. 2025 Feb 5;283:117138. doi: 10.1016/j.ejmech.2024.117138. Epub 2024 Dec 8.
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.
耐药细菌感染已成为抗感染治疗中的一项新挑战，对公众健康构成重大威胁。DNA旋转酶和拓扑异构酶IV（Topo IV）是设计新型抗生素的有前景的靶点。香桃木长期以来一直被用作防腐消毒的传统草药；然而，其抗菌活性的潜在机制仍不清楚。在本研究中，合成了一类新型桃金娘烯酮衍生物，并评估了它们对DNA旋转酶和Topo IV的抑制作用。类似物27是最有效的DNA旋转酶和Topo IV抑制剂。在生物活性测定中，分子27对耐甲氧西林金黄色葡萄球菌（MRSA）表现出显著的抗菌作用。此外，它还具有快速杀菌特性、低毒性和低诱导细菌耐药性。它与氧氟沙星、阿米卡星、头孢吡肟和头孢他啶表现出协同作用，这使其成为抗菌应用的潜在候选物。这项工作将促进基于桃金娘烯酮的DNA旋转酶和Topo IV抑制剂作为新型抗菌剂的未来开发，以应对多药耐药细菌日益普遍的情况。
