文献类型：期刊文献

英文题名：Small-molecule targeting of a diapophytoene desaturase inhibits S. aureus virulence

作者：Chen, Feifei[1];Di, Hongxia[1];Wang, Youxin[2];Cao, Qiao[1];Xu, Bin[1];Zhang, Xue[1];Yang, Nana[1];Liu, Guijie[1];Yang, Cai-Guang[1];Xu, Yong[3];Jiang, Hualiang[1];Lian, Fulin[4];Zhang, Naixia[4];Li, Jian[2];Lan, Lefu[1]

机构：[1]Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Drug Res, Shanghai 200031, Peoples R China;[2]E China Univ Sci & Technol, Sch Pharm, Shanghai Key Lab New Drug Design, Shanghai 200237, Peoples R China;[3]Humanwell Healthcare Grp Co Ltd, Wuhan, Peoples R China;[4]Chinese Acad Sci, Shanghai Inst Mat Med, Shanghai 200031, Peoples R China

年份：2016

卷号：12

期号：3

起止页码：174

外文期刊名：NATURE CHEMICAL BIOLOGY

收录：;WOS:【SCI-EXPANDED(收录号:WOS:000371377000010)】；

基金：We thank M. Wu for helpful discussion, S.F. Reichard for editing the manuscript, and F. Gotz (University of Tubingen) for providing the S. carnosus strains TM300::pTX15 and TM300::pTXcrtMN. This work was supported by the National Natural Science Foundation of China (21472207 and 31270126 to L.L.; 21222211 and 91313303 to J.L.), Hundred Talents Program of the Chinese Academy of Sciences (L.L.), Shanghai Institute of Materia Medica Foundation (CASIMM0120152018 to L.L.), Shanghai Municipal Education Commission and Shanghai Education Development Foundation (14SG28 to J.L.) and Foundation of the State Key Laboratory of Drug Research (SIMM1302KF-01 to J.L.). We acknowledge the National Science and Technology Major Project "Key New Drug Creation and Manufacturing Program" (2013ZX09507-004 to C.-G.Y.) and Shanghai Committee of Science and Technology (12ZR1453200 to F.C.).

语种：英文

摘要：The surge of antibiotic resistance in Staphylococcus aureus has created a dire need for innovative anti-infective agents that attack new targets, to overcome resistance. In S. aureus, carotenoid pigment is an important virulence factor because it shields the bacterium from host oxidant killing. Here we show that naftifine, a US Food and Drug Administration (FDA)-approved anti fungal drug, blocks biosynthesis of carotenoid pigment at nanomolar concentrations. This effect is mediated by competitive inhibition of S. aureus diapophytoene desaturase (CrtN), an essential enzyme for carotenoid pigment synthesis. We found that naftifine attenuated the virulence of a variety of clinical S. aureus isolates, including methicillin-resistant S. aureus (MRSA) strains, in mouse infection models. Specifically, we determined that naftifine is a lead compound for potent CrtN inhibitors. In sum, these findings reveal that naftifine could serve as a chemical probe to manipulate CrtN activity, providing proof of concept that CrtN is a druggable target against S. aureus infections.