Abstract
The emergence of Mycobacterium tuberculosis (MTB) strains that are resistant to most or all available antibiotics has created a severe problem for treating tuberculosis and has spurred a quest for new antibiotic targets. Here, we demonstrate that trans-translation is essential for growth of MTB and is a viable target for development of antituberculosis drugs. We also show that an inhibitor of trans-translation, KKL-35, is bactericidal against MTB under both aerobic and anoxic conditions. Biochemical experiments show that this compound targets helix 89 of the 23S rRNA. In silico molecular docking predicts a binding pocket for KKL-35 adjacent to the peptidyl-transfer center in a region not targeted by conventional antibiotics. Computational solvent mapping suggests that this pocket is a druggable hot spot for small molecule binding. Collectively, our findings reveal a new target for antituberculosis drug development and provide critical insight on the mechanism of antibacterial action for KKL-35 and related 1,3,4-oxadiazole benzamides.
Original language | English (US) |
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Pages (from-to) | 634-644 |
Number of pages | 11 |
Journal | ACS Infectious Diseases |
Volume | 3 |
Issue number | 9 |
DOIs | |
State | Published - Sep 8 2017 |
Bibliographical note
Publisher Copyright:© 2017 American Chemical Society.
Keywords
- 1,3,4-oxadiazoles
- Mycobacterium tuberculosis
- antibiotics
- ribosome rescue