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

Authors

Victoria N. Stone, Virginia Commonwealth UniversityFollow
Hardik I. Parikh, Virginia Commonwealth UniversityFollow
Fadi El-rami, Virginia Commonwealth UniversityFollow
Xiuchun Ge, Virginia Commonwealth UniversityFollow
Weihau Chen, Virginia Commonwealth University
Yan Zhang, Virginia Commonwealth UniversityFollow
Glen E. Kellogg, Virginia Commonwealth UniversityFollow
Ping Xu, Virginia Commonwealth UniversityFollow

Document Type

Article

Original Publication Date

2015

Journal/Book/Conference Title

PLoS One

Volume

10

Issue

11

DOI of Original Publication

10.1371/journal.pone.0141126

Comments

Originally published at http://dx.doi.org/10.1371/journal.pone.0141126

Date of Submission

December 2015

Abstract

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 high-throughput virtual screen method on the ZINC chemical library to select a group of potential small-molecule inhibitors. Meso-diaminopimelate dehydrogenase from P. gingivaliswas 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.

Rights

Copyright © 2015 Stone et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited

Is Part Of

VCU Philips Institute for Oral Health Research Publications