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Novel Staphyloxanthin Inhibitors with Improved Potency against Multidrug Resistant Staphylococcus aureus.

ABSTRACT: Diapophytoene desaturase (CrtN) is a potential novel target for intervening in the biosynthesis of the virulence factor staphyloxanthin. In this study, 38 1,4-benzodioxan-derived CrtN inhibitors were designed and synthesized to overwhelm the defects of leading compound 4a. Derivative 47 displayed superior pigment inhibitory activity, better hERG inhibitory properties and water solubility, and significantly sensitized MRSA strains to immune clearance in vitro. Notably, 47 displayed excellent efficacy against pigmented S. aureus Newman, Mu50 (vancomycin-intermediate MRSA, VISA), and NRS271 (linezolid-resistant MRSA, LRSA) comparable to that of linezolid and vancomycin in vivo.

SUBMITTER: Ni S

PROVIDER: S-EPMC5846034 | biostudies-literature | 2018 Mar

REPOSITORIES: biostudies-literature

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Novel Staphyloxanthin Inhibitors with Improved Potency against Multidrug Resistant Staphylococcus aureus.

Ni Shuaishuai S Li Baoli B Chen Feifei F Wei Hanwen H Mao Fei F Liu Yifu Y Xu Yixiang Y Qiu Xiaoxi X Li Xiaokang X Liu Wenwen W Hu Linghao L Ling Dazheng D Wang Manjiong M Zheng Xinyu X Zhu Jin J Lan Lefu L Li Jian J

ACS medicinal chemistry letters 20180222 3

Diapophytoene desaturase (CrtN) is a potential novel target for intervening in the biosynthesis of the virulence factor staphyloxanthin. In this study, 38 1,4-benzodioxan-derived CrtN inhibitors were designed and synthesized to overwhelm the defects of leading compound 4a. Derivative 47 displayed superior pigment inhibitory activity, better hERG inhibitory properties and water solubility, and significantly sensitized MRSA strains to immune clearance in vitro. Notably, 47 dis ...[more]

PMID: 29541366

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