Chemical Proteomics Reveals Antibiotic Targets of Oxadiazolones in MRSA

Phenotypic screening is a powerful approach to identify novel antibiotics, but elucidation of the targets responsible for the antimicrobial activity is often challenging in the case of compounds with a polypharmacological mode of action. Here, we show that activity-based protein profiling maps the target interaction landscape of a series of 1,3,4-oxadiazole-3-ones identified in a phenotypic screen to have high antibacterial potency against multidrug-resistant Staphylococcus aureus. In situ competitive and comparative chemical proteomics with a tailor-made activity-based probe, in combination with transposon and resistance studies, revealed several cysteine and serine hydrolases as relevant targets. Our data showcase oxadiazolones as a novel antibacterial chemotype with a polypharmacological mode of action, in which FabH, FphC, and AdhE play a central role.

表型筛选（Phenotypic screening）是发现新型抗生素的有效手段，但对于具有多靶点作用模式的化合物而言，阐明其抗菌活性对应的作用靶点往往颇具挑战。本研究借助基于活性的蛋白质谱分析（activity-based protein profiling），绘制了一批在表型筛选中获得、对耐多药金黄色葡萄球菌（multidrug-resistant Staphylococcus aureus）具有强效抗菌活性的1,3,4-噁二唑-3-酮类化合物的靶点相互作用全景图。本研究使用定制化基于活性的探针（activity-based probe）开展原位竞争性与比较化学蛋白质组学分析，并结合转座子突变与耐药性研究，最终鉴定出多个半胱氨酸水解酶与丝氨酸水解酶作为该类化合物的相关作用靶点。本研究数据表明，噁二唑酮类化合物是一类具备多靶点作用模式的新型抗菌化学骨架，其中FabH、FphC与AdhE发挥核心作用。