Novel Staphyloxanthin Inhibitors with Improved Potency against Multidrug Resistant Staphylococcus aureus

ACS Med Chem Lett. 2018 Feb 22;9(3):233-237. doi: 10.1021/acsmedchemlett.7b00501.

Shuaishuai Ni ¹, Baoli Li ¹, Feifei Chen ², Hanwen Wei ¹, Fei Mao ¹, Yifu Liu ¹, Yixiang Xu ¹, Xiaoxi Qiu ¹ ¹, Xiaokang Li ¹, Wenwen Liu ¹, Linghao Hu ¹, Dazheng Ling ¹, Manjiong Wang ¹, Xinyu Zheng ¹, Jin Zhu ¹, Lefu Lan ², Jian Li ¹

Affiliations

1 Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science and Technology, Shanghai 200237, China.
2 State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.

PMID: 29541366 DOI: 10.1021/acsmedchemlett.7b00501

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.

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