Discovery of NDM-1 inhibitors from natural products.

OBJECTIVES: Human health is seriously threatened by metallo-beta-lactamase(MBL)-mediated bacterial resistance. Among them, the New Delhi metallo-beta-lactamase-1(NDM-1) has received great attention due to its extensive substrate specificity and high lateral gene transfer. Currently there is no inhibitor of NDM-1 available in clinical therapy, thus making an argent need for the research and development of novel NDM-1 inhibitors.

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

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

CONCLUSION: A series of NDM-1 inhibitors were 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.