Structure-guided optimization of D-captopril for discovery of potent NDM-1 inhibitors

Guixing Ma; Sanshan Wang; Kebin Wu; Weizhe Zhang; Ashfaq Ahmad; Quan Hao; Xiaoguang Lei; Hongmin Zhang

doi:10.1016/j.bmc.2020.115902

Structure-guided optimization of D-captopril for discovery of potent NDM-1 inhibitors

Bioorg Med Chem. 2021 Jan 1:29:115902. doi: 10.1016/j.bmc.2020.115902. Epub 2020 Dec 3.

Authors

Guixing Ma¹, Sanshan Wang², Kebin Wu¹, Weizhe Zhang³, Ashfaq Ahmad¹, Quan Hao⁴, Xiaoguang Lei⁵, Hongmin Zhang⁶

Affiliations

¹ Department of Biology, Guangdong Provincial Key Laboratory of Cell Microenvironment and Disease Research and Shenzhen Key Laboratory of Cell Microenvironment, Southern University of Science and Technology, Shenzhen 518055, Guangdong, China.
² Beijing National Laboratory for Molecular Sciences, Key Laboratory of Bioorganic Chemistry and Molecular Engineering of Ministry of Education, Department of Chemical Biology, College of Chemistry and Molecular Engineering, Synthetic and Functional Biomolecules Center and Peking-Tsinghua Center for Life Sciences, Peking University, Beijing 100871, China.
³ School of Biomedical Sciences, The University of Hong Kong, Hong Kong Special Administrative Region.
⁴ School of Biomedical Sciences, The University of Hong Kong, Hong Kong Special Administrative Region. Electronic address: qhao@hku.hk.
⁵ Beijing National Laboratory for Molecular Sciences, Key Laboratory of Bioorganic Chemistry and Molecular Engineering of Ministry of Education, Department of Chemical Biology, College of Chemistry and Molecular Engineering, Synthetic and Functional Biomolecules Center and Peking-Tsinghua Center for Life Sciences, Peking University, Beijing 100871, China. Electronic address: xglei@pku.edu.cn.
⁶ Department of Biology, Guangdong Provincial Key Laboratory of Cell Microenvironment and Disease Research and Shenzhen Key Laboratory of Cell Microenvironment, Southern University of Science and Technology, Shenzhen 518055, Guangdong, China. Electronic address: zhanghm@sustech.edu.cn.

PMID: 33302045
DOI: 10.1016/j.bmc.2020.115902

Abstract

β-lactam antibiotics have long been the mainstay for the treatment of bacterial infections. New Delhi metallo-β-lactamase 1 (NDM-1) is able to hydrolyze nearly all β-lactam antibiotics and even clinically used serine-β-lactamase inhibitors. The wide and rapid spreading of NDM-1 gene among pathogenic bacteria has attracted extensive attention, therefore high potency NDM-1 inhibitors are urgently needed. Here we report a series of structure-guided design of D-captopril derivatives that can inhibit the activity of NDM-1 in vitro and at cellular levels. Structural comparison indicates the mechanisms of inhibition enhancement and provides insights for further inhibitor optimization.

Keywords: Antibiotic resistance; D-captopril derivatives; Drug discovery; Metallo-β-lactamase inhibitors; Metallo-β-lactamases (MBLs); Thiol compounds.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Anti-Bacterial Agents / chemistry*
Anti-Bacterial Agents / metabolism
Anti-Bacterial Agents / pharmacology
Bacterial Proteins / chemistry
Binding Sites
Captopril / chemistry*
Captopril / metabolism
Captopril / pharmacology
Crystallography, X-Ray
Drug Discovery
Drug Resistance, Microbial / drug effects
Humans
Hydrolysis / drug effects
Models, Molecular
Protein Binding
Structure-Activity Relationship
Sulfhydryl Compounds / chemistry
beta-Lactamase Inhibitors / chemistry*
beta-Lactamase Inhibitors / metabolism
beta-Lactamase Inhibitors / pharmacology
beta-Lactamases / metabolism*

Substances

Anti-Bacterial Agents
Bacterial Proteins
Sulfhydryl Compounds
beta-Lactamase Inhibitors
Captopril
beta-Lactamases
beta-lactamase NDM-1