title: Small-molecule targeting of a diapophytoene desaturase inhibits S. aureus virulence.
abstract: 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 antifungal 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.
authors.affiliation: State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China.
authors.forename: Feifei
authors.identifier: http://orcid.org/0000-0002-7251-1956
authors.initials: F
authors.lastname: Chen
authors.affiliation: State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China.
authors.forename: Hongxia
authors.initials: H
authors.lastname: Di
authors.affiliation: Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science and Technology, Shanghai, China.
authors.forename: Youxin
authors.initials: Y
authors.lastname: Wang
authors.affiliation: State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China.
authors.forename: Qiao
authors.initials: Q
authors.lastname: Cao
authors.affiliation: State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China.
authors.forename: Bin
authors.initials: B
authors.lastname: Xu
authors.affiliation: State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China.
authors.forename: Xue
authors.initials: X
authors.lastname: Zhang
authors.affiliation: State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China.
authors.forename: Nana
authors.initials: N
authors.lastname: Yang
authors.affiliation: State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China.
authors.forename: Guijie
authors.initials: G
authors.lastname: Liu
authors.affiliation: State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China.
authors.forename: Cai-Guang
authors.initials: CG
authors.lastname: Yang
authors.affiliation: Humanwell Healthcare (Group) Co. Ltd., Wuhan, China.
authors.forename: Yong
authors.initials: Y
authors.lastname: Xu
authors.affiliation: State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China.
authors.forename: Hualiang
authors.initials: H
authors.lastname: Jiang
authors.affiliation: Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China.
authors.forename: Fulin
authors.initials: F
authors.lastname: Lian
authors.affiliation: Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China.
authors.forename: Naixia
authors.initials: N
authors.lastname: Zhang
authors.affiliation: Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science and Technology, Shanghai, China.
authors.forename: Jian
authors.initials: J
authors.lastname: Li
authors.affiliation: State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China.
authors.forename: Lefu
authors.identifier: http://orcid.org/0000-0002-5551-5496
authors.initials: L
authors.lastname: Lan
mesh_terms: D000499:Allylamine / Q000031:analogs & derivatives* / Q000494:pharmacology; D000818:Animals; D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D001426:Bacterial Proteins / Q000037:antagonists & inhibitors*; D001667:Binding, Competitive / Q000187:drug effects; D002338:Carotenoids / Q000378:metabolism; D015195:Drug Design; D024881:Drug Resistance, Bacterial; D055624:Methicillin-Resistant Staphylococcus aureus / Q000187:drug effects; D051379:Mice; D008826:Microbial Sensitivity Tests; D010088:Oxidoreductases / Q000037:antagonists & inhibitors*; D013203:Staphylococcal Infections / Q000188:drug therapy / Q000382:microbiology; D013211:Staphylococcus aureus / Q000187:drug effects* / Q000201:enzymology / Q000472:pathogenicity; D037521:Virulence Factors; D024341:Xanthophylls / Q000037:antagonists & inhibitors / Q000096:biosynthesis
chemical_list: D000900:Anti-Bacterial Agents; D001426:Bacterial Proteins; D037521:Virulence Factors; D024341:Xanthophylls; D002338:Carotenoids; D000499:Allylamine; C029178:naftifine; C031841:staphyloxanthin; C091055:CrtN protein, Staphylococcus aureus; D010088:Oxidoreductases