75650-93-0Relevant articles and documents
Identification of small-molecule inhibitors against Meso-2, 6-diaminopimelate dehydrogenase from porphyromonas gingivalis
Stone, Victoria N.,Parikh, Hardik I.,El-Rami, Fadi,Ge, Xiuchun,Chen, Weihau,Zhang, Yan,Kellogg, Glen E.,Xu, Ping
, (2016/01/09)
Species-specific antimicrobial therapy has the potential to combat the increasing threat of antibiotic resistance and alteration of the human microbiome. We therefore set out to demonstrate the beginning of a pathogen-selective drug discovery method using the periodontal pathogen Porphyromonas gingivalis as a model. Through our knowledge of metabolic networks and essential genes we identified a "druggable" essential target, meso-diaminopimelate dehydrogenase, which is found in a limited number of species. We adopted a highthroughput virtual screen method on the ZINC chemical library to select a group of potential small-molecule inhibitors. Meso-diaminopimelate dehydrogenase from P. gingivalis was first expressed and purified in Escherichia coli then characterized for enzymatic inhibitor screening studies. Several inhibitors with similar structural scaffolds containing a sulfonamide core and aromatic substituents showed dose-dependent inhibition. These compounds were further assayed showing reasonable whole-cell activity and the inhibition mechanism was determined. We conclude that the establishment of this target and screening strategy provides a model for the future development of new antimicrobials.
