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Ribosome Rescue Inhibitors Kill Actively Growing and Nonreplicating Persister Mycobacterium Tuberculosis Cells

Ribosome Rescue Inhibitors Kill Actively Growing and Nonreplicating Persister Mycobacterium Tuberculosis Cells

John N Alumasa, Paolo S Manzanillo, Nicholas D Peterson, Tricia Lundrigan, Anthony D Baughn, Jeffery S Cox, Kenneth C Keiler

ACS Infect Dis. 2017 Sep 8;3(9):634-644.

PMID: 28762275

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.

Chemicals Related in the Paper:

Catalog Number	Product Name	Structure	CAS Number	Price
AP865285296	KKL-35		865285-29-6	Price

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