Identification of novel inhibitors of bacterial translation elongation factors.
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.
Jayasekera
Maithri M K
MM
Johnson and Johnson Pharmaceutical Research and Development, 3210 Merryfield Row, San Diego, CA 92121, USA.
Onheiber
Keysha
K
Keith
John
J
Venkatesan
Hariharan
H
Santillan
Alejandro
A
Stocking
Emily M
EM
Tang
Liu
L
Miller
Jennifer
J
Gomez
Leslie
L
Rhead
Brooke
B
Delcamp
Tavner
T
Huang
Shaoming
S
Wolin
Ronald
R
Bobkova
Ekaterina V
EV
Shaw
Karen Joy
KJ
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
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