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A genetic strategy to identify targets for the development of drugs that prevent bacterial persistence.

TitleA genetic strategy to identify targets for the development of drugs that prevent bacterial persistence.
Publication TypeJournal Article
Year of Publication2013
AuthorsKim J-H, O'Brien KM, Sharma R, Boshoff HIM, Rehren G, Chakraborty S, Wallach JB, Monteleone M, Wilson DJ, Aldrich CC, Barry CE, Rhee KY, Ehrt S, Schnappinger D
JournalProc Natl Acad Sci U S A
Volume110
Issue47
Pagination19095-100
Date Published2013 Nov 19
ISSN1091-6490
KeywordsAmide Synthases, Animals, Carrier Proteins, Drug Discovery, Drug Tolerance, Escherichia coli Proteins, Gene Expression Regulation, Enzymologic, Genetic Engineering, Luciferases, Mice, Mycobacterium tuberculosis, Tuberculosis
Abstract

Antibacterial drug development suffers from a paucity of targets whose inhibition kills replicating and nonreplicating bacteria. The latter include phenotypically dormant cells, known as persisters, which are tolerant to many antibiotics and often contribute to failure in the treatment of chronic infections. This is nowhere more apparent than in tuberculosis caused by Mycobacterium tuberculosis, a pathogen that tolerates many antibiotics once it ceases to replicate. We developed a strategy to identify proteins that Mycobacterium tuberculosis requires to both grow and persist and whose inhibition has the potential to prevent drug tolerance and persister formation. This strategy is based on a tunable dual-control genetic switch that provides a regulatory range spanning three orders of magnitude, quickly depletes proteins in both replicating and nonreplicating mycobacteria, and exhibits increased robustness to phenotypic reversion. Using this switch, we demonstrated that depletion of the nicotinamide adenine dinucleotide synthetase (NadE) rapidly killed Mycobacterium tuberculosis under conditions of standard growth and nonreplicative persistence induced by oxygen and nutrient limitation as well as during the acute and chronic phases of infection in mice. These findings establish the dual-control switch as a robust tool with which to probe the essentiality of Mycobacterium tuberculosis proteins under different conditions, including those that induce antibiotic tolerance, and NadE as a target with the potential to shorten current tuberculosis chemotherapies.

DOI10.1073/pnas.1315860110
Alternate JournalProc Natl Acad Sci U S A
PubMed ID24191058
PubMed Central IDPMC3839782
Grant ListR56 AI089911 / AI / NIAID NIH HHS / United States
AI089911 / AI / NIAID NIH HHS / United States
/ / Intramural NIH HHS / United States

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