title: Identification of Small-Molecule Inhibitors against Meso-2, 6-Diaminopimelate Dehydrogenase from Porphyromonas gingivalis.
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.
authors.affiliation: 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.
authors.forename: Victoria N
authors.initials: VN
authors.lastname: Stone
authors.affiliation: Department of Medicinal Chemistry, Virginia Commonwealth University, Richmond, Virginia, United States of America.
authors.forename: Hardik I
authors.initials: HI
authors.lastname: Parikh
authors.affiliation: 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.
authors.forename: Fadi
authors.initials: F
authors.lastname: El-rami
authors.affiliation: Philips Institute for Oral Health Research, Virginia Commonwealth University, Richmond, Virginia, United States of America.
authors.forename: Xiuchun
authors.initials: X
authors.lastname: Ge
authors.affiliation: Philips Institute for Oral Health Research, Virginia Commonwealth University, Richmond, Virginia, United States of America.
authors.forename: Weihau
authors.initials: W
authors.lastname: Chen
authors.affiliation: Department of Medicinal Chemistry, Virginia Commonwealth University, Richmond, Virginia, United States of America.
authors.forename: Yan
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: 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.
authors.forename: Glen E
authors.initials: GE
authors.lastname: Kellogg
authors.affiliation: 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.
authors.forename: Ping
authors.initials: P
authors.lastname: Xu
mesh_terms: D000594:Amino Acid Oxidoreductases / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D000595:Amino Acid Sequence; D000900:Anti-Bacterial Agents / Q000737:chemistry / Q000494:pharmacology*; D016866:Bacteroidaceae Infections / Q000188:drug therapy* / Q000201:enzymology / Q000382:microbiology; D003001:Cloning, Molecular; D004926:Escherichia coli / Q000187:drug effects / Q000201:enzymology*; D057166:High-Throughput Screening Assays / Q000379:methods*; D006801:Humans; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009249:NADP / Q000378:metabolism; D016966:Porphyromonas gingivalis / Q000187:drug effects* / Q000201:enzymology*; D011487:Protein Conformation; D017386:Sequence Homology, Amino Acid; D054852:Small Molecule Libraries / Q000737:chemistry / Q000494:pharmacology*; D013379:Substrate Specificity
chemical_list: D000900:Anti-Bacterial Agents; D054852:Small Molecule Libraries; D009249:NADP; D000594:Amino Acid Oxidoreductases; C020032:diaminopimelate dehydrogenase