Discovery of NDM-1 inhibitors from natural products

Abstract

Objectives: Human health is seriously threatened by metallo-β-lactamase (MBL)-mediated bacterial antimicrobial resistance, among which New Delhi metallo-β-lactamase 1 (NDM-1) has received great attention due to its extensive substrate profile and high lateral gene transfer. Currently, there is no inhibitor of NDM-1 available in clinical therapy, thus making an urgent need for research and development of novel NDM-1 inhibitors.

Methods: A natural compound library was screened to determine potential inhibitors of NDM-1 based on its crystal structure. Five known NDM-1 inhibitors were used as positive controls for the computer screening protocol. Based on the screening results, the half maximal inhibitory concentration (IC₅₀) of several potential NDM-1 inhibitors was determined using purified NDM-1. The potential interaction between the inhibitor and NDM-1 was analysed using docking.

Results: Five potential NDM-1 inhibitors were discovered with IC₅₀ values ranging from 3.348±1.35μM (hesperidin) to 214.1±13.37μM (stevioside). The most active inhibitor, hesperidin, acts directly on key residues near the NDM-1 active site.

Conclusion: A series of NDM-1 inhibitors was discovered using virtual screening, which allows for improved screening efficiency and reduced costs. Considering the low toxicity of these compounds, they may be used as potential lead compounds for the development of NDM-1 inhibitors.

Keywords: Multidrug resistance; NDM-1 inhibitors; Natural products; Virtual screening; β-Lactams.