Journal
MOLECULAR CELL
Volume 62, Issue 2, Pages 284-294Publisher
CELL PRESS
DOI: 10.1016/j.molcel.2016.03.035
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Funding
- Bill & Melinda Gates Foundation
- Peking University 985 fund
- National Natural Science Foundation of China [31370847, 31327901]
- Recruitment Program of Global Youth Experts
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Natural variations in gene expression provide a mechanism for multiple phenotypes to arise in an isogenic bacterial population. In particular, a subgroup termed persisters show high tolerance to antibiotics. Previously, their formation has been attributed to cell dormancy. Here we demonstrate that bacterial persisters, under beta-lactam antibiotic treatment, show less cytoplasmic drug accumulation as a result of enhanced efflux activity. Consistently, a number of multi-drug efflux genes, particularly the central component TolC, show higher expression in persisters. Time-lapse imaging and mutagenesis studies further establish a positive correlation between tolC expression and bacterial persistence. The key role of efflux systems, among multiple biological pathways involved in persister formation, indicates that persisters implement a positive defense against antibiotics prior to a passive defense via dormancy. Finally, efflux inhibitors and antibiotics together effectively attenuate persister formation, suggesting a combination strategy to target drug tolerance.
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