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

Kim, Jee-Hyun, O'Brien, Kathryn M., Sharma, Ritu, Boshoff, Helena I. M., Rehren, German, Chakraborty, Sumit, Wallach, Joshua B., Monteleone, Mercedes, Wilson, Daniel J., Aldrich, Courtney C., Barry, Clifton E., III, Rhee, Kyu Y., Ehrt, Sabine and Schnappinger, Dirk (2013) A genetic strategy to identify targets for the development of drugs that prevent bacterial persistence. Proceedings of the National Academy of Sciences of the United States of America, 110 47: 19095-19100. doi:10.1073/pnas.1315860110


Author Kim, Jee-Hyun
O'Brien, Kathryn M.
Sharma, Ritu
Boshoff, Helena I. M.
Rehren, German
Chakraborty, Sumit
Wallach, Joshua B.
Monteleone, Mercedes
Wilson, Daniel J.
Aldrich, Courtney C.
Barry, Clifton E., III
Rhee, Kyu Y.
Ehrt, Sabine
Schnappinger, Dirk
Title A genetic strategy to identify targets for the development of drugs that prevent bacterial persistence
Journal name Proceedings of the National Academy of Sciences of the United States of America   Check publisher's open access policy
ISSN 0027-8424
1091-6490
Publication date 2013-11-19
Sub-type Article (original research)
DOI 10.1073/pnas.1315860110
Open Access Status Not yet assessed
Volume 110
Issue 47
Start page 19095
End page 19100
Total pages 6
Place of publication Washington, DC, United States
Publisher National Academy of Sciences
Language eng
Formatted 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.
Q-Index Code C1
Q-Index Status Provisional Code
Institutional Status Non-UQ

Document type: Journal Article
Sub-type: Article (original research)
Collection: Institute for Molecular Bioscience - Publications
 
Versions
Version Filter Type
Citation counts: TR Web of Science Citation Count  Cited 35 times in Thomson Reuters Web of Science Article | Citations
Scopus Citation Count Cited 38 times in Scopus Article | Citations
Google Scholar Search Google Scholar
Created: Sat, 04 Mar 2017, 01:00:43 EST by Web Cron on behalf of Learning and Research Services (UQ Library)