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Science 334 (6058): 982-986

Copyright © 2011 by the American Association for the Advancement of Science

Active Starvation Responses Mediate Antibiotic Tolerance in Biofilms and Nutrient-Limited Bacteria

Dao Nguyen,1,{dagger} Amruta Joshi-Datar,2 Francois Lepine,3 Elizabeth Bauerle,2 Oyebode Olakanmi,4 Karlyn Beer,2 Geoffrey McKay,1 Richard Siehnel,2 James Schafhauser,1 Yun Wang,5 Bradley E. Britigan,4,6,* Pradeep K. Singh2

Abstract: Bacteria become highly tolerant to antibiotics when nutrients are limited. The inactivity of antibiotic targets caused by starvation-induced growth arrest is thought to be a key mechanism producing tolerance. Here we show that the antibiotic tolerance of nutrient-limited and biofilm Pseudomonas aeruginosa is mediated by active responses to starvation, rather than by the passive effects of growth arrest. The protective mechanism is controlled by the starvation-signaling stringent response (SR), and our experiments link SR-mediated tolerance to reduced levels of oxidant stress in bacterial cells. Furthermore, inactivating this protective mechanism sensitized biofilms by several orders of magnitude to four different classes of antibiotics and markedly enhanced the efficacy of antibiotic treatment in experimental infections.

1 Departments of Medicine, Microbiology and Immunology,McGill University, 1650 Cedar Avenue, L11.513, Montreal, Quebec H3G 1A4, Canada.
2 Departments of Medicine and Microbiology, University of Washington School of Medicine, 1959 Northeast Pacific Street, Seattle, WA 98195–7242, USA.
3 Department of Microbiology, INRS Armand Frappier, 531 Boulevarde des Prairies, Laval, Quebec H7V 1B7, Canada.
4 Department of Internal Medicine, University of Cincinnati, Medical Sciences Building 6065, Post Office Box 670557, Cincinnati, OH 45267, USA.
5 Department of Civil and Environmental Engineering, Northwestern University, A222 Technological Institute, 2145 Sheridan Road, Evanston, IL 60208, USA.
6 Veterans Administration Medical Center–Cincinnati, 3200 Vine Street, Cincinnati, OH 45220, USA.

* Present address: College of Medicine, University of Nebraska, 42nd and Emile, Omaha, NE 68198, USA.

{dagger} To whom correspondence should be addressed. E-mail: dao.nguyen{at}

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