Document Type


Original Publication Date


Journal/Book/Conference Title

PLoS One





DOI of Original Publication



Originally published at

Date of Submission

December 2015


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.


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

S1_Fig.tif (980 kB)
SDS PAGE analysis of purified protein.

S2_Fig.tif (311 kB)
Dose-dependent analysis of unsaturated analogs of m-DAP against P. gingivalis m-Ddh.

S3_Fig.tif (321 kB)
Characterization of kinetic properties of P. gingivalis m-Ddh.

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