Recent research and development of NDM-1 inhibitors

Bacteria carrying New Delhi metallo-beta-lactamase-1 (New Delhi metallo-beta-lactamase, NDM-1) resistance gene is a new type of superbug, which can hydrolyze almost all beta-lactam antibiotics, rapidly spread among the same species and even spread among different species. NDM-1 belongs to the class B1 broad-spectrum enzyme of beta-lactamase. The two positively charged zinc ions in the active center have electrostatic interaction with the hydroxyl ions in them to seize the hydrogen atom near the water molecule to form a bridging ring water molecule, which strengthens its nucleophilicity and attacks the carbonyl group on the lactam ring; thus, catalyzing the hydrolysis of beta-lactam antibiotics. Since NDM-1 has an open active site and unique electrostatic structure, it essentially provides a wider range of substrate specificity. Due to its flexible hydrolysis mechanism and more and more variants also aggravate the threat of drug-resistant bacteria infection, there is still no effective inhibitor in clinic, which is a serious threat to human health and public health safety. The electron-rich substituents of NDM-1 inhibitors coordinate with two positively charged zinc ions in the active center of the enzyme through ion-dipole interaction to produce NDM-1 inhibitory activity. In this review, the research progress of NDM-1 enzyme and its inhibitors in the past 5 years was reviewed. The crystal structure, active center structure, surrounding important amino acid residues, newly discovered inhibitors and their action mechanism are classified and summarized in detail, which can be used as a reference for the development of effective drugs against drug-resistant bacteria targeting NDM-1. (C) 2021 Published by Elsevier Masson SAS.

Automated summary

Bacteria carrying the New Delhi metallo-beta-lactamase-1 (NDM-1) resistance gene are a new type of superbug, with the ability to rapidly spread and exhibit broader substrate specificity, posing a serious threat to human health and public health safety due to their strong antibiotic resistance.