Premium
Benzimidazole and Benzoxazole Zinc Chelators as Inhibitors of Metallo‐β‐Lactamase NDM‐1
Author(s) -
Jackson Abigail C.,
Pinter Tyler B. J.,
Talley Daniel C.,
BakerAgha Adnan,
Patel Dhruvil,
Smith Paul J.,
Franz Katherine J.
Publication year - 2021
Publication title -
chemmedchem
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.817
H-Index - 100
eISSN - 1860-7187
pISSN - 1860-7179
DOI - 10.1002/cmdc.202000607
Subject(s) - benzimidazole , chemistry , benzoxazole , pharmacophore , docking (animal) , zinc , combinatorial chemistry , ternary complex , enzyme , antibacterial activity , antibiotics , antimicrobial , stereochemistry , biochemistry , bacteria , biology , organic chemistry , medicine , nursing , genetics
Bacterial expression of β‐lactamases, which hydrolyze β‐lactam antibiotics, contributes to the growing threat of antibacterial drug resistance. Metallo‐β‐lactamases, such as NDM‐1, use catalytic zinc ions in their active sites and hydrolyze nearly all clinically available β‐lactam antibiotics. Inhibitors of metallo‐β‐lactamases are urgently needed to overcome this resistance mechanism. Zinc‐binding compounds are promising leads for inhibitor development, as many NDM‐1 inhibitors contain zinc‐binding pharmacophores. Here, we evaluated 13 chelating agents containing benzimidazole and benzoxazole scaffolds as NDM‐1 inhibitors. Six of the compounds showed potent inhibitory activity with IC 50 values as low as 0.38 μM, and several compounds restored the meropenem susceptibility of NDM‐1‐expressing E. coli . Spectroscopic and docking studies suggest ternary complex formation as the mechanism of inhibition, making these compounds promising for development as NDM‐1 inhibitors.