title: Identification of low-molecular-weight compounds inhibiting growth of corynebacteria: potential lead compounds for antibiotics.
abstract: The bacterial genus Corynebacteria contains several pathogenic species that cause diseases such as diphtheria in humans and "cheesy gland" in goats and sheep. Thus, identifying new therapeutic targets to treat Corynebacteria infections is both medically and economically important. CG2496, a functionally uncharacterized protein from Corynebacterium glutamicum, was evaluated using an NMR ligand-affinity screen. A total of 11 compounds from a library of 460 biologically active compounds were shown to selectively bind CG2496 in a highly conserved region of the protein. The best binder was identified to be methiothepin (KD =54 ± 19 µM), an FDA-approved serotonin receptor antagonist. Methiothepin was also shown to inhibit the growth of C. glutamicum, but not bacteria that lack CG2496 homologs. Our results suggest that CG2496 is a novel therapeutic target and methiothepin is a potential lead compound or structural scaffold for developing new antibiotics specifically targeting Corynebacteria.
authors.affiliation: Department of Chemistry, University of Nebraska-Lincoln, Lincoln, NE 68588-0304 (USA).
authors.forename: Jaime L
authors.initials: JL
authors.lastname: Stark
authors.forename: Jennifer C
authors.initials: JC
authors.lastname: Copeland
authors.forename: Alexander
authors.initials: A
authors.lastname: Eletsky
authors.forename: Greg A
authors.initials: GA
authors.lastname: Somerville
authors.forename: Thomas
authors.initials: T
authors.lastname: Szyperski
authors.forename: Robert
authors.initials: R
authors.lastname: Powers
mesh_terms: D000818:Animals; D000900:Anti-Bacterial Agents / Q000737:chemistry* / Q000494:pharmacology*; D001426:Bacterial Proteins / Q000737:chemistry / Q000378:metabolism*; D003352:Corynebacterium / Q000737:chemistry / Q000187:drug effects* / Q000254:growth & development / Q000378:metabolism; D003354:Corynebacterium Infections / Q000188:drug therapy* / Q000662:veterinary*; D055808:Drug Discovery; D006041:Goats; D006801:Humans; D008024:Ligands; D009682:Magnetic Resonance Spectroscopy; D008719:Methiothepin / Q000737:chemistry / Q000494:pharmacology; D008958:Models, Molecular; D012756:Sheep; D054852:Small Molecule Libraries / Q000737:chemistry / Q000494:pharmacology
chemical_list: D000900:Anti-Bacterial Agents; D001426:Bacterial Proteins; D008024:Ligands; D054852:Small Molecule Libraries; D008719:Methiothepin
keywords: Corynebacteria; FAST-NMR; NMR spectroscopy; antibiotics; drug discovery