title: Identification of novel inhibitors of bacterial translation elongation factors.
abstract: Bacterial elongation factor Tu (EF-Tu) and EF-Ts are interacting proteins involved in polypeptide chain elongation in protein biosynthesis. A novel scintillation proximity assay for the detection of inhibitors of EF-Tu and EF-Ts, as well as the interaction between them, was developed and used in a high-throughput screen of a chemical library. Several compounds from a variety of chemical series with inhibitory properties were identified, including certain indole dipeptides, benzimidazole amidines, 2-arylbenzimidazoles, N-substituted imidazoles, and N-substituted guanidines. The in vitro activities of these compounds were confirmed in a coupled bacterial transcription-translation assay. Several indole dipeptides were identified as inhibitors of bacterial translation, with compound 2 exhibiting a 50% inhibitory concentration of 14 microM and an MIC for S. aureus ATCC 29213 of 5.6 microg/ml. Structure-activity relationship studies around the dipeptidic indoles generated additional analogs with low micromolar MICs for both gram-negative and gram-positive bacteria. To assess the specificity of antibacterial action, these compounds were evaluated in a metabolic labeling assay with Staphylococcus aureus. Inhibition of translation, as well as limited effects on other macromolecular pathways for some of the analogs studied, indicated a possible contribution from a non-target-based antibacterial mechanism of action.
authors.affiliation: Johnson and Johnson Pharmaceutical Research and Development, 3210 Merryfield Row, San Diego, CA 92121, USA.
authors.forename: Maithri M K
authors.initials: MM
authors.lastname: Jayasekera
authors.forename: Keysha
authors.initials: K
authors.lastname: Onheiber
authors.forename: John
authors.initials: J
authors.lastname: Keith
authors.forename: Hariharan
authors.initials: H
authors.lastname: Venkatesan
authors.forename: Alejandro
authors.initials: A
authors.lastname: Santillan
authors.forename: Emily M
authors.initials: EM
authors.lastname: Stocking
authors.forename: Liu
authors.initials: L
authors.lastname: Tang
authors.forename: Jennifer
authors.initials: J
authors.lastname: Miller
authors.forename: Leslie
authors.initials: L
authors.lastname: Gomez
authors.forename: Brooke
authors.initials: B
authors.lastname: Rhead
authors.forename: Tavner
authors.initials: T
authors.lastname: Delcamp
authors.forename: Shaoming
authors.initials: S
authors.lastname: Huang
authors.forename: Ronald
authors.initials: R
authors.lastname: Wolin
authors.forename: Ekaterina V
authors.initials: EV
authors.lastname: Bobkova
authors.forename: Karen Joy
authors.initials: KJ
authors.lastname: Shaw
mesh_terms: D000900:Anti-Bacterial Agents / Q000737:chemistry* / Q000494:pharmacology; D001562:Benzimidazoles / Q000737:chemistry / Q000494:pharmacology; D004151:Dipeptides / Q000737:chemistry* / Q000494:pharmacology*; D006090:Gram-Negative Bacteria / Q000187:drug effects; D006095:Gram-Positive Cocci / Q000187:drug effects; D006146:Guanidines / Q000737:chemistry / Q000494:pharmacology; D007093:Imidazoles / Q000737:chemistry / Q000494:pharmacology; D007211:Indoles / Q000737:chemistry*; D046911:Macromolecular Substances / Q000378:metabolism; D008826:Microbial Sensitivity Tests; D010444:Peptide Elongation Factor Tu / Q000037:antagonists & inhibitors* / Q000378:metabolism; D010445:Peptide Elongation Factors / Q000037:antagonists & inhibitors* / Q000378:metabolism; D014176:Protein Biosynthesis / Q000187:drug effects; D013329:Structure-Activity Relationship; D014158:Transcription, Genetic / Q000187:drug effects
chemical_list: D000900:Anti-Bacterial Agents; D001562:Benzimidazoles; D004151:Dipeptides; D006146:Guanidines; D007093:Imidazoles; D007211:Indoles; D046911:Macromolecular Substances; D010445:Peptide Elongation Factors; C023512:elongation factor Ts; C030374:indole; D010444:Peptide Elongation Factor Tu