Chemistry Department, Institute for Drug Discovery, Purdue University, West Lafayette, Indiana 47907, United States.
Department of Biomedical Sciences and Pathobiology, Virginia-Maryland College of Veterinary Medicine, Virginia Polytechnic Institute and State University, Blacksburg, Virginia 24060, United States.
J Med Chem. 2022 May 12;65(9):6612-6630. doi: 10.1021/acs.jmedchem.1c02034. Epub 2022 Apr 28.
Methicillin-resistant (MRSA) infections are still difficult to treat, despite the availability of many FDA-approved antibiotics. Thus, new compound scaffolds are still needed to treat MRSA. The oxadiazole-containing compound, , has been shown to reduce lipoteichoic acid (LTA) in , but the mechanism that accounts for LTA biosynthesis inhibition remains uncharacterized. Herein, we report the elucidation of the mechanism by which inhibits LTA biosynthesis via utilization of global proteomics, activity-based protein profiling, and lipid analysis via multiple reaction monitoring (MRM). Our data suggest that inhibits LTA biosynthesis via direct binding to PgcA and downregulation of PgsA. We further show that reduces the MRSA load in skin infection (mouse) and decreases pro-inflammatory cytokines in MRSA-infected wounds. Collectively, merits further consideration as a potential drug for staphylococcal infections.
耐甲氧西林金黄色葡萄球菌（MRSA）感染仍然难以治疗，尽管有许多获得 FDA 批准的抗生素。因此，仍然需要新的化合物支架来治疗 MRSA。含恶二唑的化合物 已被证明可以减少 中的脂磷壁酸（LTA），但尚不清楚其抑制 LTA 生物合成的机制。在此，我们通过利用全蛋白质组学、基于活性的蛋白质谱分析和通过多重反应监测（MRM）进行脂质分析，报告了 通过抑制 LTA 生物合成的机制阐明。我们的数据表明， 通过直接结合 PgcA 并下调 PgsA 来抑制 LTA 生物合成。我们进一步表明， 减少皮肤感染（小鼠）中的 MRSA 负荷，并减少 MRSA 感染伤口中的促炎细胞因子。总的来说， 作为治疗葡萄球菌感染的潜在药物值得进一步考虑。
