Staphylococcus aureus is the leading cause of infections worldwide, and methicillin-resistant strains (MRSA) are emerging. New strategies are urgently needed to overcome this threat. Using a cell-based screen of ~45,000 diverse synthetic compounds, we discovered a potent bioactive, MAC-545496, that reverses β-lactam resistance in the community-acquired MRSA USA300 strain. MAC-545496 could also serve as an antivirulence agent alone; it attenuates MRSA virulence in Galleria mellonella larvae. MAC-545496 inhibits biofilm formation and abrogates intracellular survival in macrophages. Mechanistic characterization revealed MAC-545496 to be a nanomolar inhibitor of GraR, a regulator that responds to cell-envelope stress and is an important virulence factor and determinant of antibiotic resistance. The small molecule discovered herein is an inhibitor of GraR function. MAC-545496 has value as a research tool to probe the GraXRS regulatory system and as an antibacterial lead series of a mechanism to combat drug-resistant Staphylococcal infections.

中文翻译：

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发现一种逆转MRSA中β-内酰胺抗性的抗毒化合物。

金黄色葡萄球菌是全世界感染的主要原因，并且耐甲氧西林的菌株（MRSA）正在出现。迫切需要新的策略来克服这一威胁。使用基于细胞的约45,000种不同合成化合物的筛选，我们发现了一种有效的生物活性物质MAC-545496，可逆转社区获得的MRSA USA300菌株中的β-内酰胺抗性。MAC-545496也可以单独用作抗毒剂；它减弱了Malleria mellonella幼虫中的MRSA毒力。MAC-545496抑制生物膜的形成并消除巨噬细胞的细胞内存活。机理表征表明，MAC-545496是GraR的纳摩尔抑制剂，它是一种对细胞包膜应力作出反应的调节剂，是重要的毒力因子和抗生素耐药性的决定因素。本文发现的小分子是GraR功能的抑制剂。MAC-545496作为研究GraXRS调控系统的研究工具以及对抗耐药性葡萄球菌感染的机制的抗菌先导系列具有价值。