<i>Mycobacterium tuberculosis</i> is a natural mutant with an inactivated oxidative‐stress regulatory gene:implications for sensitivity to isoniazid

Deretić, Vojo; Philipp, W.; Dhandayuthapani, Subramanian; Mudd, Michal H.; Curcic, R.; Garbe, Thomas R.; Heym, Béate; Via, Laura E.; Cole, Stewart T.

doi:10.1111/j.1365-2958.1995.mmi_17050889.x

Cited by 170 publications

(173 citation statements)

References 32 publications

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“…Within Mycobacterium tuberculosis, however, o x y R is inactivated by multiple lesions. These findings refuted the initial assumption that the transcription of the mycobacterial katG gene is under the control of an OxyR-type regulator (Deretic et a[., 1995). In the course of sequencing projects, several furA genes could be identified within different mycobacteria, the deduced proteins of which are closely related to Streptomyces reticuli Furs.…”

Section: Discussioncontrasting

confidence: 32%

The mycelium-associated Streptomyces reticuli catalase-peroxidase, its gene and regulation by FurS

Zou¹,

Borovok²,

Lucana³

et al. 1999

Microbiology

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During early stages of growth, Streptomyces reticuli synthesizes a hyphaeassociated, haem-containing enzyme which exhibits catalase and peroxidase activities with broad substrate specificity (CpeB). The purified dimeric enzyme (160 kDa) consists of two identical subunits. Using anti-CpeB antibodies and an expression-as well as a mini-library, the corresponding cpeB gene was identified and sequenced. It encodes a protein of 740 aa with a molecular mass of 81.3 kDa. The deduced protein shares the highest level of amino acid identity with KatG from Caulobacter crescentus and Mycobacterium tuberculosis, and PerA from Bacillus stearothermophilus. Streptomyces lividans transformants carrying cpeB and the upstream-located furs gene with its regulatory region on the bifunctional vector pWHM3 produced low or enhanced levels of CpeB in the presence or absence of Fe ions, respectively. An in-frame deletion of the major part of furs induces increased CpeB synthesis. The data imply that Furs regulates the transcription of cpeB. The deduced Furs protein is rich in histidine residues, contains a putative N-terminally situated helix-turn-helix motif and has a molecular mass of 15.1 kDa. It shares only 29% amino acid identity with the Escherichia coli ferric uptake regulator (Fur) protein, but about 64% with FurA deduced from the genomic sequences of several mycobacteria. The predicted secondary structures of Furs and FurA are highly similar and considerably divergent from those of the E. coli Fur. In contrast to some Gram-negative bacteria, within several mycobacteria an intact furA gene or a furA pseudogene is upstream of a catalase-peroxidase (katG) gene predicted to encode a functional or a non-functional (Mycobacterium leprae) enzyme. Thus the data obtained for Streptomyces reticuli are expected to serve as an additional model to elucidate the regulation of mycobacterial catalase-peroxidase genes.1

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Section: Discussioncontrasting

confidence: 32%

The mycelium-associated Streptomyces reticuli catalase-peroxidase, its gene and regulation by FurS

Zou¹,

Borovok²,

Lucana³

et al. 1999

Microbiology

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“…OxyR is present in most mycobacteria and has been shown in Mycobacterium marinum to positively regulate expression of ahpC but not of katG (37). A striking finding was that in M. tuberculosis, oxyR is inactivated by multiple mutations, resulting in minimal basal or inducible expression of ahpC in this organism (10,45). In M. smegmatis and M. tuberculosis, katG was recently shown to be cotranscribed with and regulated by furA, which encodes a repressor similar to Fur proteins in many bacteria (41,54).…”

Section: Vol 183 2001mentioning

confidence: 99%

“…More recent molecular investigation has linked these phenotypes to the genes encoding catalase/peroxidase (katG) and alkylhydroperoxidase (ahpC) in M. tuberculosis (48,52,55,56). Strikingly, the gene encoding OxyR, a positive regulator of the peroxide stress response in other bacteria and in most other mycobacterial species, was found to be inactivated by multiple mutations in M. tuberculosis, suggesting altered regulation of the oxidative-stress response in this pathogen (10,45).…”

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confidence: 99%

The Alternative Sigma Factor SigH Regulates Major Components of Oxidative and Heat Stress Responses inMycobacterium tuberculosis

et al. 2001

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Mycobacterium tuberculosis is a specialized intracellular pathogen that must regulate gene expression to overcome stresses produced by host defenses during infection. SigH is an alternative sigma factor that we have previously shown plays a role in the response to stress of the saprophyte Mycobacterium smegmatis. In this work we investigated the role of sigH in the M. tuberculosis response to heat and oxidative stress. We determined that a M. tuberculosis sigH mutant is more susceptible to oxidative stresses and that the inducible expression of the thioredoxin reductase/thioredoxin genes trxB2/trxC and a gene of unknown function, Rv2466c, is regulated by sigH via expression from promoters directly recognized by SigH. We also determined that the sigH mutant is more susceptible to heat stress and that inducible expression of the heat shock genes dnaK and clpB is positively regulated by sigH. The induction of these heat shock gene promoters but not of other SigH-dependent promoters was markedly greater in response to heat versus oxidative stress, consistent with their additional regulation by a heat-labile repressor. To further understand the role of sigH in the M. tuberculosis stress response, we investigated the regulation of the stress-responsive sigma factor genes sigE and sigB. We determined that inducible expression of sigE is regulated by sigH and that basal and inducible expression of sigB is dependent on sigE and sigH. These data indicate that sigH plays a central role in a network that regulates heat and oxidative-stress responses that are likely to be important in M. tuberculosis pathogenesis.Tuberculosis remains a major cause of human suffering, exacting an enormous toll of morbidity and mortality in much of the world (11). The cause of tuberculosis, the obligate pathogen Mycobacterium tuberculosis, is highly adapted for survival in the host organism. Following infection M. tuberculosis is ingested by macrophages and must persist in this environment in order to survive, either in a quiescent state or through active replication that results in tissue destruction and the disease of tuberculosis. In adapting to this intracellular environment, this bacterium must regulate its physiology to survive a variety of stresses produced by the macrophage, including reactive oxygen and reactive nitrogen species produced by these cells (1, 4, 28). In addition M. tuberculosis has been shown to alter the physiology of the macrophage to modulate host defenses (51). Although the sequencing of the M. tuberculosis genome and recent insights are beginning to shed light on pathogenic mechanisms of this organism (7,8,27,30), the means by which M. tuberculosis adapts to survive and replicate in the host remain poorly understood.Data from a number of laboratories have implicated several alternative sigma factors of mycobacteria, including SigB, SigE, SigF, and SigH, in the adaptation of the pathogen M. tuberculosis and the saprophyte Mycobacterium smegmatis to several stresses (5,9,12,20,29,53). M. smegmatis SigH has been shown ...

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“…It has been shown recently that M . tu6erculosis is naturally deficient in the oxidative stress response present in most mycobacterial species (Deretic et al, 1995;Sherman et al, 1995;Dhandayuthapani et al, 1996); thus it is likely that M . tu6erculosis cannot efficiently eliminate these toxic oxygen derivatives.…”

Section: Katg Is Involved In Radioactivity Accumulation At the Uptakementioning

confidence: 99%

Mechanism of isoniazid uptake in Mycobacterium tuberculosis

et al. 1998

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Initial transport kinetics of isoniazid (INH) and its uptake a t the plateau were studied in Mycobacterium tuberculosis H37Rv under various experimental conditions. The initial uptake velocity increased linearly with INH concentration from 2 x lom6 M to M. It was modified neither by addition of a protonophore that abolished proline transport, nor following ATP depletion by arsenate, which inhibited glycerol uptake, two transport processes taken as controls for secondary active transport and facilitated diffusion, respectively. Microaerobiosis or low temperature (4 "C) were without effect on initial uptake. It is thus likely that INH transport in M. tuberculosis proceeds by a passive diffusion mechanism, and that catalase-peroxidase (KatG) is not involved in the actual transport. However, conditions inhibiting KatG activity (high INH concentration, microaerobiosis, low temperature) decrease cell radioactivity a t the uptake plateau. It is proposed that INH transport occurs by passive diffusion. KatG is involved only in the intracellular accumulation of oxidized derivatives of INH, especially of isonicotinic acid, which is trapped inside cells in its ionized form. This model explains observed and previously known characteristics of the accumulation of radioactivity in the presence of [14C]INH for various species and strains of mycobacteria.

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Mycobacterium tuberculosis is a natural mutant with an inactivated oxidative‐stress regulatory gene:implications for sensitivity to isoniazid

Cited by 170 publications

References 32 publications

The mycelium-associated Streptomyces reticuli catalase-peroxidase, its gene and regulation by FurS

The mycelium-associated Streptomyces reticuli catalase-peroxidase, its gene and regulation by FurS

The Alternative Sigma Factor SigH Regulates Major Components of Oxidative and Heat Stress Responses inMycobacterium tuberculosis

Mechanism of isoniazid uptake in Mycobacterium tuberculosis

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