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Antimicrobial Agents and Chemotherapy, June 2007, p. 2092-2099, Vol. 51, No. 6
0066-4804/07/$08.00+0     doi:10.1128/AAC.00052-07
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

PhoU Is a Persistence Switch Involved in Persister Formation and Tolerance to Multiple Antibiotics and Stresses in Escherichia coli{triangledown} ,{dagger}

Yongfang Li and Ying Zhang*

Department of Molecular Microbiology and Immunology, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, Maryland 21205

Received 14 January 2007/ Returned for modification 2 March 2007/ Accepted 30 March 2007

When a bactericidal antibiotic is added to a growing bacterial culture, the great majority of the bacterial population is killed but a small number of metabolically quiescent bacteria called persisters survive antibiotic treatment. The mechanism of this bacterial persistence is poorly understood. In Escherichia coli, we identified a new persistence gene, phoU, whose inactivation leads to a generalized higher susceptibility than that of the parent strain to a diverse range of antibiotics, including ampicillin, norfloxacin, and gentamicin, and stresses, such as starvation, acid pH, heat, peroxide, weak acids, and energy inhibitors, especially in stationary phase. The PhoU mutant phenotype could be complemented by a functional phoU gene. Mutation in PhoU leads to a metabolically hyperactive status of the cell, as shown by an increased expression of energy production genes, flagella, and chemotaxis genes and a defect in persister formation. PhoU, whose expression is regulated by environmental changes like nutrient availability and age of culture, is a global negative regulator beyond its role in phosphate metabolism and facilitates persister formation by the suppression of many important cellular metabolic processes. A new model of persister formation based on PhoU as a persister switch is proposed. PhoU may be an ideal drug target for designing new drugs that kill persister bacteria for more effective control of bacterial infections.

* Corresponding author. Mailing address: Department of Molecular Microbiology and Immunology, Bloomberg School of Public Health, Johns Hopkins University, 615 N. Wolfe Street, Baltimore, MD 21205. Phone: (410) 614-2975. Fax: (410) 955-0105. E-mail: yzhang{at}jhsph.edu

{triangledown} Published ahead of print on 9 April 2007.

{dagger} Supplemental material for this article may be found at http://aac.asm.org/.

Antimicrobial Agents and Chemotherapy, June 2007, p. 2092-2099, Vol. 51, No. 6
0066-4804/07/$08.00+0     doi:10.1128/AAC.00052-07
Copyright © 2007, American Society for Microbiology. All Rights Reserved.



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