Download MendeleyStructure-Based Development of (1-(3'-Mercaptopropanamido)methyl)boronic Acid Derived Broad-Spectrum, Dual-Action Inhibitors of Metallo- and Serine-beta-lactamases.
Wang, Y.L., Liu, S., Yu, Z.J., Lei, Y., Huang, M.Y., Yan, Y.H., Ma, Q., Zheng, Y., Deng, H., Sun, Y., Wu, C., Yu, Y., Chen, Q., Wang, Z., Wu, Y., Li, G.B.(2019) J Med Chem 62: 7160-7184
- PubMed: 31269398
- DOI: https://doi.org/10.1021/acs.jmedchem.9b00735
- Primary Citation of Related Structures:
6J8Q, 6J8R, 6JN3, 6JN4, 6JN5, 6JN6 - PubMed 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.
Organizational Affiliation:
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.
