Structure-Based Development of (1-(3'-Mercaptopropanamido)methyl)boronic Acid Derived Broad-Spectrum, Dual-Action Inhibitors of Metallo- and Serine-β-lactamases

  • J Med Chem. 2019 Aug 8;62(15):7160-7184. doi: 10.1021/acs.jmedchem.9b00735.
Yao-Ling Wang  1 ,  Sha Liu  1 ,  Zhu-Jun Yu  1 ,  Yuan Lei  1 ,  Meng-Yi Huang  1 ,  Yu-Hang Yan  1 ,  Qiang Ma  1 ,  Yang Zheng  1 ,  Hui Deng  2 ,  Ying Sun  2 ,  Chengyong Wu  2 ,  Yamei Yu  2 ,  Qiang Chen  2 ,  Zhenling Wang  2 ,  Yong Wu  1 ,  Guo-Bo Li  1
Affiliations
  • 1. Key Laboratory of Drug-Targeting and Drug Delivery System of the Education Ministry, Sichuan Engineering Laboratory for Plant-Sourced Drug and Sichuan Research Center for Drug Precision Industrial Technology, West China School of Pharmacy , Sichuan University , Sichuan 610041 , China.
  • 2. State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, West China Medical School , Sichuan University , Chengdu 610041 , China.
PMID: 31269398 DOI: 10.1021/acs.jmedchem.9b00735
Abstract

The emergence and spread of Bacterial pathogens acquired metallo-β-lactamase (MBL) and serine-β-lactamase (SBL) medicated β-lactam resistance gives rise to an urgent need for the development of new dual-action MBL/SBL inhibitors. Application of a pharmacophore fusion strategy led to the identification of (2'S)-(1-(3'-mercapto-2'-methylpropanamido)methyl)boronic acid (MS01) as a new dual-action inhibitor, which manifests broad-spectrum inhibition to representative MBL/SBL Enzymes, including the widespread VIM-2 and KPC-2. Guided by the VIM-2:MS01 and KPC-2:MS01 complex structures, further structural optimization yielded new, more potent dual-action inhibitors. Selectivity studies indicated that the inhibitors had no apparent inhibition to human angiotensin-converting enzyme-2 and showed selectivity across serine hydrolyases in E. coli and human HEK293T cells labeled by the activity-based probe TAMRA-FP. Moreover, the inhibitors displayed potentiation of meropenem efficacy against MBL- or SBL-positive clinical isolates without apparent cytotoxicity. This work will aid efforts to develop new types of clinically useful dual-action inhibitors targeting MBL/SBL Enzymes.

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