2. Academic Validation
  3. Structure-guided optimization of D-captopril for discovery of potent NDM-1 inhibitors

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.
Guixing Ma 1,  Sanshan Wang 2,  Kebin Wu 1,  Weizhe Zhang 3,  Ashfaq Ahmad 1,  Quan Hao 4,  Xiaoguang Lei 5,  Hongmin Zhang 6
Affiliations

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: [email protected].
  • 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: [email protected].
  • 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: [email protected].
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.

Figures
Products