Molecular and physiological effects of mycobacterial oxyR inactivation.
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.
Department of Microbiology, University of Michigan Medical School, Ann Arbor, Michigan 48105, USA.
Eileen
E
Pagán-Ramos
Sharon S
SS
Master
Christopher L
CL
Pritchett
Renate
R
Reimschuessel
Michele
M
Trucksis
Graham S
GS
Timmins
Vojo
V
Deretic
D000818:Animals; D000995:Antitubercular Agents / Q000494:pharmacology; D001426:Bacterial Proteins / Q000235:genetics / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000378:metabolism*; D024881:Drug Resistance, Bacterial; D005393:Fish Diseases / Q000382:microbiology; D017353:Gene Deletion; D006054:Goldfish; D007538:Isoniazid / Q000494:pharmacology; D019910:Mycobacterium marinum / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D018384:Oxidative Stress; D010545:Peroxides; D012097:Repressor Proteins / Q000378:metabolism*; D014157:Transcription Factors / Q000378:metabolism*
D000995:Antitubercular Agents; D001426:Bacterial Proteins; D004268:DNA-Binding Proteins; D010545:Peroxides; D012097:Repressor Proteins; D014157:Transcription Factors; D007538:Isoniazid