Mycobacterial FurA is a negative regulator of catalase-peroxidase gene katG.
In several bacteria, the catalase-peroxidase gene katG is under positive control by oxyR, a transcriptional regulator of the peroxide stress response. The Mycobacterium tuberculosis genome also contains sequences corresponding to oxyR, but this gene has been inactivated in the tubercle bacillus because of the presence of multiple mutations and deletions. Thus, M. tuberculosis katG and possibly other parts of the oxidative stress response in this organism are either not regulated or are controlled by a factor different from OxyR. The mycobacterial FurA is a homologue of the ferric uptake regulator Fur and is encoded by a gene located immediately upstream of katG. Here, we examine the possibility that FurA regulates katG expression. Inactivation of furA on the Mycobacterium smegmatis chromosome, a mycobacterial species that also lacks an oxyR homologue, resulted in derepression of katG, concomitant with increased resistance of the furA mutant to H2O2. In addition, M. smegmatis furA::Km(r) was more sensitive to the front-line antituberculosis agent isonicotinic acid hydrazide (INH) compared with the parental furA+ strain. The phenotypic manifestations were specific, as the mutant strain did not show altered sensitivity to organic peroxides, and both H2O2 and INH susceptibility profiles were complemented by the wild-type furA+ gene. We conclude that FurA is a second regulator of oxidative stress response in mycobacteria and that it negatively controls katG. In species lacking a functional oxyR, such as M. tuberculosis and M. smegmatis, FurA appears to be a dominant regulator affecting mycobacterial physiology and intracellular survival.
Department of Microbiology and Immunology, University of Michigan Medical School, Medical Science Building II, Ann Arbor, MI 48109, USA.
T C
TC
Zahrt
J
J
Song
J
J
Siple
V
V
Deretic
D001426:Bacterial Proteins / Q000235:genetics* / Q000378:metabolism; D001555:Benzene Derivatives / Q000494:pharmacology; D015964:Gene Expression Regulation, Bacterial; D006861:Hydrogen Peroxide / Q000494:pharmacology; D007501:Iron / Q000378:metabolism; D007538:Isoniazid; D008969:Molecular Sequence Data; D020102:Mycobacterium smegmatis / Q000187:drug effects / Q000201:enzymology* / Q000235:genetics / Q000254:growth & development; D010544:Peroxidases / Q000235:genetics* / Q000378:metabolism*; D054464:Peroxiredoxins; D012097:Repressor Proteins / Q000235:genetics* / Q000378:metabolism
D001426:Bacterial Proteins; D001555:Benzene Derivatives; D012097:Repressor Proteins; C068477:ferric uptake regulating proteins, bacterial; D006861:Hydrogen Peroxide; D007501:Iron; D010544:Peroxidases; D054464:Peroxiredoxins; C076136:catalase HPI; C007164:cumene hydroperoxide; D007538:Isoniazid