Journal
ACS INFECTIOUS DISEASES
Volume 3, Issue 9, Pages 634-644Publisher
AMER CHEMICAL SOC
DOI: 10.1021/acsinfecdis.7b00028
Keywords
Mycobacterium tuberculosis; antibiotics; 1,3,4-oxadiazoles; ribosome rescue
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Funding
- NIH [GM068720, AI132275, DP1AI124619, AI123146]
- Bill and Melinda Gates Foundation
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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.
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