Data.zip

The global rise in antimicrobial resistance (AMR) is a critical public health issue, with methicillin-resistant <i>Staphylococcus aureus</i> (MRSA) being a key player. MRSA causes severe infections, including pneumonia and septic arthritis. This study investigates MgrA, a transcription factor that regulates <i>S. aureus</i> multidrug resistance and virulence, identifying negletein as a potent MgrA inhibitor. Negletein's ability to modulate virulence without directly killing bacteria introduces a novel strategy to combat multidrug resistance. It disrupts <i>S. aureus</i> adhesion and invasion by interfering with the Agr system and altering surface protein expression, preventing infection. Additionally, negletein enhances host immune responses by increasing neutrophil chemotaxis. Confirmed through thermal shift assays and fluorescence quenching, negletein’s interaction with MgrA reveals key binding residues. In vitro and in vivo studies demonstrated that negletein offers dose-dependent protection against MRSA, significantly improving survival rates and reducing bacterial burden in infection models. Notably, negletein showed therapeutic effects on MRSA-induced septic arthritis. These findings underscore negletein's potential as a novel treatment for MRSA-induced infections, providing an innovative approach to tackle multidrug-resistant infections and advancing new paradigms in AMR treatment.

全球抗菌药物耐药性（antimicrobial resistance, AMR）的日益蔓延已成为重大公共卫生议题，其中耐甲氧西林金黄色葡萄球菌（methicillin-resistant Staphylococcus aureus, MRSA）是关键致病菌之一。MRSA可引发包括肺炎、化脓性关节炎在内的重症感染。本研究针对调控金黄色葡萄球菌多药耐药性与毒力的转录因子MgrA展开探究，鉴定出negletein为强效MgrA抑制剂。negletein无需直接杀灭细菌即可调控病原菌毒力，为对抗多药耐药性提供了全新策略；该化合物通过干扰Agr系统、改变表面蛋白表达，破坏金黄色葡萄球菌的黏附与侵袭能力，从而阻断感染。此外，negletein可通过增强中性粒细胞趋化作用，强化宿主免疫应答。经热位移测定法与荧光猝灭实验证实，negletein与MgrA的相互作用及其关键结合残基得以明确。体外与体内实验结果表明，negletein可对MRSA感染发挥剂量依赖性保护作用，在感染模型中显著提升宿主存活率并降低细菌负荷。尤为值得注意的是，negletein对MRSA诱导的化脓性关节炎具有治疗效果。上述研究结果凸显了negletein作为MRSA感染新型治疗手段的潜力，为应对多药耐药菌感染提供了创新思路，同时推动抗菌药物耐药性治疗领域的范式革新。