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Identification of Small-Molecule Inhibitors against Meso-2, 6-Diaminopimelate Dehydrogenase from Porphyromonas gingivalis
- Source :
- PLoS ONE, PLoS ONE, Vol 10, Iss 11, p e0141126 (2015)
- Publication Year :
- 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. 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.
- Subjects :
- Models, Molecular
Protein Conformation
Molecular Sequence Data
Druggability
lcsh:Medicine
Dehydrogenase
Biology
medicine.disease_cause
Microbiology
Chemical library
Substrate Specificity
Small Molecule Libraries
chemistry.chemical_compound
medicine
Bacteroidaceae Infections
Escherichia coli
Humans
Amino Acid Sequence
Cloning, Molecular
lcsh:Science
Porphyromonas gingivalis
chemistry.chemical_classification
Multidisciplinary
Sequence Homology, Amino Acid
Drug discovery
lcsh:R
biology.organism_classification
Anti-Bacterial Agents
High-Throughput Screening Assays
Enzyme
chemistry
Biochemistry
Diaminopimelate dehydrogenase
lcsh:Q
Amino Acid Oxidoreductases
NADP
Research Article
Subjects
Details
- ISSN :
- 19326203
- Volume :
- 10
- Issue :
- 11
- Database :
- OpenAIRE
- Journal :
- PloS one
- Accession number :
- edsair.doi.dedup.....57bb085a47a62bc9fe19260a2b24379b