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

Autor:	Stone VN; Philips Institute for Oral Health Research, Virginia Commonwealth University, Richmond, Virginia, United States of America.; Department of Microbiology and Immunology, Virginia Commonwealth University, Richmond, Virginia, United States of America., Parikh HI; Department of Medicinal Chemistry, Virginia Commonwealth University, Richmond, Virginia, United States of America., El-rami F; Philips Institute for Oral Health Research, Virginia Commonwealth University, Richmond, Virginia, United States of America.; Department of Microbiology and Immunology, Virginia Commonwealth University, Richmond, Virginia, United States of America., Ge X; Philips Institute for Oral Health Research, Virginia Commonwealth University, Richmond, Virginia, United States of America., Chen W; Philips Institute for Oral Health Research, Virginia Commonwealth University, Richmond, Virginia, United States of America., Zhang Y; Department of Medicinal Chemistry, Virginia Commonwealth University, Richmond, Virginia, United States of America., Kellogg GE; Department of Medicinal Chemistry, Virginia Commonwealth University, Richmond, Virginia, United States of America.; Center for the Study of Biological Complexity, Virginia Commonwealth University, Richmond, Virginia, United States of America., Xu P; Philips Institute for Oral Health Research, Virginia Commonwealth University, Richmond, Virginia, United States of America.; Department of Microbiology and Immunology, Virginia Commonwealth University, Richmond, Virginia, United States of America.; Center for the Study of Biological Complexity, Virginia Commonwealth University, Richmond, Virginia, United States of America.
Jazyk:	angličtina
Zdroj:	PloS one [PLoS One] 2015 Nov 06; Vol. 10 (11), pp. e0141126. Date of Electronic Publication: 2015 Nov 06 (Print Publication: 2015).
DOI:	10.1371/journal.pone.0141126
Abstrakt:	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. 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.
Databáze:	MEDLINE
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