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

• Published in: Journal of medicinal chemistry 2019-08, Vol.62 (15), p.7160-7184
• Main Authors: Wang, Yao-Ling, Liu, Sha, Yu, Zhu-Jun, Lei, Yuan, Huang, Meng-Yi, Yan, Yu-Hang, Ma, Qiang, Zheng, Yang, Deng, Hui, Sun, Ying, Wu, Chengyong, Yu, Yamei, Chen, Qiang, Wang, Zhenling, Wu, Yong, Li, Guo-Bo
• Format: Article
• Language: English
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/acs.jmedchem.9b00735

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.