Guo Weikai, Zhao Yanyang, Yang Yuqing, Li Wenyu, Wang Kexiao, Zhou Fang, Li Jiaqi, Li Xiangfeng, Zhang Yuan, Hu Biao, Zhang Wenwen, Wei Xin, Li Qiming
Henan Province EngineeringTechnology Research Center of Rapid-Accuracy Medical Diagnostics, Department of Clinical Laboratory, the First Affiliated Hospital of Henan University, Henan University, Kaifeng, 475000, China.
The Jointed National Laboratory of Antibody Drug Engineering, the First Affiliated Hospital of Henan University, Henan University, Kaifeng, 475000, China.
BMC Microbiol. 2025 Nov 11;25(1):728. doi: 10.1186/s12866-025-04475-6.
The global rise of antibiotic resistance presents a critical public health challenge, with being a leading cause of hospital- and community-acquired infections. Methicillin-resistant (MRSA) is particularly concerning due to its high prevalence, multidrug resistance, and association with severe morbidity and mortality. Developing novel small-molecule antimicrobial agents with reduced resistance susceptibility is essential to combat these infections.
From our in-house compound library, we identified YZ462, a heteroaromatic-aryl scaffold compound, demonstrating potent antibacterial activity and low toxicity. YZ462 showed strong anti-MRSA effects through bacterial membrane disruption, increased permeability, and induction of endogenous ROS production. In vitro, it effectively killed both log-phase and stationary-phase MRSA while inhibiting biofilm formation and disrupting established biofilms. In vivo studies revealed significant reduction of bacterial loads and improved survival rates in infected animal models. Importantly, the major membrane component cardiolipin (CL) directly interacted with YZ462 and attenuated its antibacterial activity, suggesting CL as a potential molecular target.
Our study establishes YZ462 as a promising small-molecule candidate for MRSA treatment, featuring a unique mechanism of membrane disruption and ROS induction. These results confirm its potent antimicrobial activity and demonstrate therapeutic potential against MRSA infections.
The online version contains supplementary material available at 10.1186/s12866-025-04475-6.
抗生素耐药性在全球范围内的上升是一项严峻的公共卫生挑战，是医院获得性感染和社区获得性感染的主要原因。耐甲氧西林金黄色葡萄球菌（MRSA）因其高流行率、多重耐药性以及与严重发病率和死亡率的关联而尤其令人担忧。开发具有降低耐药易感性的新型小分子抗菌剂对于对抗这些感染至关重要。
从我们内部的化合物库中，我们鉴定出YZ462，一种杂芳基 - 芳基支架化合物，具有强大的抗菌活性和低毒性。YZ462通过破坏细菌膜、增加通透性和诱导内源性活性氧生成显示出强大的抗MRSA作用。在体外，它能有效杀死对数期和静止期的MRSA，同时抑制生物膜形成并破坏已形成的生物膜。体内研究表明，感染动物模型中的细菌载量显著降低，存活率提高。重要的是，主要的膜成分心磷脂（CL）直接与YZ462相互作用并减弱其抗菌活性，表明CL是一个潜在的分子靶点。
我们的研究将YZ462确立为一种有前景的用于治疗MRSA的小分子候选物，其具有独特的膜破坏和活性氧诱导机制。这些结果证实了其强大的抗菌活性，并证明了其对MRSA感染的治疗潜力。
在线版本包含可在10.1186/s12866-025-04475-6获取的补充材料。
