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Journal of Bacteriology, April 2006, p. 2674-2680, Vol. 188, No. 7
0021-9193/06/$08.00+0     doi:10.1128/JB.188.7.2674-2680.2006
Copyright © 2006, American Society for Microbiology. All Rights Reserved.

Molecular and Physiological Effects of Mycobacterial oxyR Inactivation

Eileen Pagán-Ramos,1 Sharon S. Master,2 Christopher L. Pritchett,3 Renate Reimschuessel,4 Michele Trucksis,5 Graham S. Timmins,6* and Vojo Deretic2,7

Department of Microbiology, University of Michigan Medical School, Ann Arbor, Michigan 48105,1 Department of Molecular Genetics and Microbiology,2 School of Pharmacy,6 Department of Cell Biology and Physiology, University of New Mexico Health Sciences Center, Albuquerque, New Mexico 87131,7 Department of Microbiology and Immunology, University of Maryland School of Medicine, Baltimore, Maryland 21201,3 Center for Veterinary Medicine, Food and Drug Administration, Laurel, Maryland 20857,4 Department of Medicine, University of Massachusetts Medical School, Worcester, Massachusetts 016055

Received 16 September 2005/ Accepted 13 January 2006

The majority of slow-growing mycobacteria have a functional oxyR, the central regulator of the bacterial oxidative stress response. In contrast, this gene has been inactivated during the evolution of Mycobacterium tuberculosis. Here we inactivated the oxyR gene in Mycobacterium marinum, an organism used to model M. tuberculosis pathogenesis. Inactivation of oxyR abrogated induction of ahpC, a gene encoding alkylhydroperoxide reductase, normally activated upon peroxide challenge. The absence of oxyR also resulted in increased sensitivity to the front-line antituberculosis drug isoniazid. Inactivation of oxyR in M. marinum did not affect either virulence in a fish infection model or survival in human macrophages. Our findings demonstrate, at the genetic and molecular levels, a direct role for OxyR in ahpC regulation in response to oxidative stress. Our study also indicates that oxyR is not critical for virulence in M. marinum. However, oxyR inactivation confers increased sensitivity to isonicotinic acid hydrazide, suggesting that the natural loss of oxyR in the tubercle bacillus contributes to the unusually high sensitivity of M. tuberculosis to isoniazid.

* Corresponding author. Mailing address: College of Pharmacy, University of New Mexico Health Sciences Center, 915 Camino de Salud, NE, Albuquerque, NM 87131. Phone: (505) 272-4103. Fax: (505) 272-6749. E-mail: gtimmins{at}salud.unm.edu.

Journal of Bacteriology, April 2006, p. 2674-2680, Vol. 188, No. 7
0021-9193/06/$08.00+0     doi:10.1128/JB.188.7.2674-2680.2006
Copyright © 2006, American Society for Microbiology. All Rights Reserved.



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