title: Discovery of Benzocycloalkane Derivatives Efficiently Blocking Bacterial Virulence for the Treatment of Methicillin-Resistant S. aureus (MRSA) Infections by Targeting Diapophytoene Desaturase (CrtN).
abstract: Antivirulence strategies are now attracting interest for the inherent mechanism of action advantages. In our previous work, diapophytoene desaturase (CrtN) was identified to be an attractive and drugable target for fighting pigmented S. aureus infections. In this research, we developed a series of effective benzocycloalkane-derived CrtN inhibitors with submicromolar IC50. Analogue 8 blocked the pigment biosynthesis of three MRSA strains with a nanomolar IC50 value. Corresponding to its mode of action, 8 did not function as a bactericidal agent. 8 could sensitize S. aureus to immune clearance. In vivo, 8 was proven to be efficacious in an S. aureus Newman sepsis model and abscess formation model. For two typical MRSAs, USA400 MW2 and Mu50, 8 significantly decreased the staphylococcal loads in the liver and kidneys. Moreover, 8 showed minimal antifungal activity compared to that of NTF. In summary, 8 has the potential to be developed as a therapeutic drug, especially against intractable MRSA issues.
authors.affiliation: Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science and Technology , Shanghai 200237, 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 201203, China.
authors.forename: Hongxia
authors.initials: H
authors.lastname: Di
authors.affiliation: State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences , Shanghai 201203, China.
authors.forename: Feifei
authors.initials: F
authors.lastname: Chen
authors.affiliation: Hubei Bio-pharmaceutical Industrial Technological Institute, Inc. , Wuhan 430075, China.
authors.forename: Yong
authors.initials: Y
authors.lastname: Xu
authors.affiliation: Hubei Bio-pharmaceutical Industrial Technological Institute, Inc. , Wuhan 430075, China.
authors.forename: Qiang
authors.initials: Q
authors.lastname: Xiao
authors.affiliation: Humanwell Healthcare (Group) Co., Ltd. , Wuhan 430075, China.
authors.forename: Xuehai
authors.initials: X
authors.lastname: Wang
authors.affiliation: Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science and Technology , Shanghai 200237, China.
authors.forename: Hanwen
authors.initials: H
authors.lastname: Wei
authors.affiliation: Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science and Technology , Shanghai 200237, China.
authors.forename: Yanli
authors.initials: Y
authors.lastname: Lu
authors.affiliation: Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science and Technology , Shanghai 200237, China.
authors.forename: Lingling
authors.initials: L
authors.lastname: Zhang
authors.affiliation: Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science and Technology , Shanghai 200237, China.
authors.forename: Jin
authors.initials: J
authors.lastname: Zhu
authors.affiliation: State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences , Shanghai 201203, China.
authors.forename: Lefu
authors.initials: L
authors.lastname: Lan
authors.affiliation: Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science and Technology , Shanghai 200237, China.
authors.forename: Jian
authors.initials: J
authors.lastname: Li
mesh_terms: D000473:Alkanes / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D000900:Anti-Bacterial Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D000935:Antifungal Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D055808:Drug Discovery; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D005658:Fungi / Q000187:drug effects; D055624:Methicillin-Resistant Staphylococcus aureus / Q000187:drug effects* / Q000201:enzymology / Q000254:growth & development; D008826:Microbial Sensitivity Tests; D015394:Molecular Structure; D010088:Oxidoreductases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013203:Staphylococcal Infections / Q000188:drug therapy*; D013329:Structure-Activity Relationship
chemical_list: D000473:Alkanes; D000900:Anti-Bacterial Agents; D000935:Antifungal Agents; D004791:Enzyme Inhibitors; D010088:Oxidoreductases