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

Research output: Contribution to journalArticle

9 Scopus citations

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 languageEnglish (US)
Pages (from-to)634-644
Number of pages11
JournalACS Infectious Diseases
Volume3
Issue number9
DOIs
StatePublished - Sep 8 2017

All Science Journal Classification (ASJC) codes

  • Infectious Diseases

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