Identification of Small-Molecule Inhibitors against <i>Meso</i>-2, 6-Diaminopimelate Dehydrogenase from <i>Porphyromonas gingivalis</i>

Abstract

<div><p>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 <i>Porphyromonas gingivalis</i> as a model. Through our knowledge of metabolic networks and essential genes we identified a “druggable” essential target, <i>meso</i>-diaminopimelate dehydrogenase, which is found in a limited number of species. We adopted a high-throughput virtual screen method on the ZINC chemical library to select a group of potential small-molecule inhibitors. <i>Meso</i>-diaminopimelate dehydrogenase from <i>P</i>. <i>gingivalis</i> was first expressed and purified in <i>Escherichia coli</i> 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.</p></div