Serine hydrolases play diverse roles in regulating host–pathogen interactions in a number of organisms, yet few have been characterized in the human pathogen Staphylococcus aureus. Here we describe a chemical proteomic screen that identified ten previously uncharacterized S. aureus serine hydrolases that mostly lack human homologs. We termed these enzymes fluorophosphonate-binding hydrolases (FphA–J). One hydrolase, FphB, can process short fatty acid esters, exhibits increased activity in response to host cell factors, is located predominantly on the bacterial cell surface in a subset of cells, and is concentrated in the division septum. Genetic disruption of fphB confirmed that the enzyme is dispensable for bacterial growth in culture but crucial for establishing infection in distinct sites in vivo. A selective small molecule inhibitor of FphB effectively reduced infectivity in vivo, suggesting that it may be a viable therapeutic target for the treatment or management of Staphylococcus infections.

丝氨酸水解酶在许多生物体中调节宿主与病原体的相互作用中起着不同的作用，但在人类病原体金黄色葡萄球菌中却很少被表征。在这里，我们描述了一种化学蛋白质组学筛选方法，该方法可以鉴定出十种以前缺乏特征的金黄色葡萄球菌丝氨酸水解酶，这些酶大多缺乏人类同源性。我们称这些酶为氟磷酸盐结合水解酶（FphA–J）。一种水解酶FphB可以处理短脂肪酸酯，对宿主细胞因子有反应，显示出增强的活性，主要位于部分细胞的细菌细胞表面，并且集中在分裂间隔中。fphB的遗传破坏证实该酶对于培养物中细菌的生长是必不可少的，但对于在体内不同部位建立感染至关重要。FphB的选择性小分子抑制剂可有效降低体内的感染性，表明它可能是治疗或管理葡萄球菌感染的可行治疗靶标。