Sigma Factors: Key Molecules in
            <i>Mycobacterium tuberculosis</i>
            Physiology and Virulence

Manganelli, Riccardo

doi:10.1128/microbiolspec.mgm2-0007-2013

Cited by 45 publications

(32 citation statements)

References 160 publications

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“…Alternative sigma factors are master regulators of bacterial gene expression and are known to be involved in several aspects of bacterial physiology (16). In this study, we found that at least two mycobacterial sigma factors, SigE and SigB, are involved in determining the basal level of resistance of M. tuberculosis to antitubercular drugs and the amount of persisters able to survive drug treatment.…”

Section: Discussionmentioning

confidence: 76%

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The Alternative Sigma Factors SigE and SigB Are Involved in Tolerance and Persistence to Antitubercular Drugs

Pisu

Provvedi

Espinosa

et al. 2017

Antimicrob Agents Chemother

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The emergence and spread of drug-resistant Mycobacterium tuberculosis strains possibly threaten our ability to treat this disease in the future. Even though two new antitubercular drugs have recently been introduced, there is still the need to design new molecules whose mechanisms of action could reduce the length of treatment. We show that two alternative sigma factors of M. tuberculosis (SigE and SigB) have a major role in determining the level of basal resistance to several drugs and the amount of persisters surviving long-duration drug treatment. We also demonstrate that ethambutol, a bacteriostatic drug, is highly bactericidal for M. tuberculosis mutants missing either SigE or SigB. We suggest that molecules able to interfere with the activity of SigE or SigB not only could reduce M. tuberculosis virulence in vivo but also could boost the effect of other drugs by increasing the sensitivity of the organism and reducing the number of persisters able to escape killing.

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Section: Discussionmentioning

confidence: 76%

“…SigE represents one of the major players in the M. tuberculosis stress response and has a fundamental role in the adaptation to surface and oxidative stresses (16,17). During antibiotic treatment, bacteria are subjected to several stresses (including oxidative and surface stresses), depending on the drug's mechanism of action (18)(19)(20)(21).…”

Section: Resultsmentioning

confidence: 99%

The Alternative Sigma Factors SigE and SigB Are Involved in Tolerance and Persistence to Antitubercular Drugs

Pisu

Provvedi

Espinosa

et al. 2017

Antimicrob Agents Chemother

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“…Anti-sigma factors may be transmembrane proteins, e.g., M. tuberculosis RslA (the anti-sigma factor of SigL), or cytoplasmic proteins, e.g., M. tuberculosis RshA (anti-sigma factor of SigH), and thus may transduce either extra-cytoplasmic or intracellular signals ( 5 , 6 ). Sigma factors and their regulatory mechanisms are discussed in depth in reference 139 .…”

mentioning

confidence: 99%

Mycobacterium tuberculosis Serine/Threonine Protein Kinases

Prisic

Husson

2014

Microbiol Spectr

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The Mycobacterium tuberculosis genome encodes 11 serine/threonine protein kinases (STPKs). A similar number of two-component systems are also present, indicating that these two signal transduction mechanisms are both important in the adaptation of this bacterial pathogen to its environment. The M. tuberculosis phosphoproteome includes hundreds of Ser- and Thr-phosphorylated proteins that participate in all aspects of M. tuberculosis biology, supporting a critical role for the STPKs in regulating M. tuberculosis physiology. Nine of the STPKs are receptor type kinases, with an extracytoplasmic sensor domain and an intracellular kinase domain, indicating that these kinases transduce external signals. Two other STPKs are cytoplasmic and have regulatory domains that sense changes within the cell. Structural analysis of some of the STPKs has led to advances in our understanding of the mechanisms by which these STPKs are activated and regulated. Functional analysis has provided insights into the effects of phosphorylation on the activity of several proteins, but for most phosphoproteins the role of phosphorylation in regulating function is unknown. Major future challenges include characterizing the functional effects of phosphorylation for this large number of phosphoproteins, identifying the cognate STPKs for these phosphoproteins, and determining the signals that the STPKs sense. Ultimately, combining these STPK-regulated processes into larger, integrated regulatory networks will provide deeper insight into M. tuberculosis adaptive mechanisms that contribute to tuberculosis pathogenesis. Finally, the STPKs offer attractive targets for inhibitor development that may lead to new therapies for drug-susceptible and drug-resistant tuberculosis.

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“…Mycobacterium smegmatis and Mycobacterium tuberculosis encode 28 and 13 different sigma factors, respectively, but SigA, the sole group 1 member in each species, is essential and is presumably responsible for expression of all or most housekeeping genes (4). Multiple types of promoter specificities have also been reported, and although the correspondence with specific sigma factors is incomplete, the SigA promoters have similarity to the Sig-70 promoters of Escherichia coli.…”

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confidence: 99%

“…T ranscriptional regulation in mycobacteria is complex, with many different sigma factors and promoter sequences (1)(2)(3)(4)(5). Mycobacterium smegmatis and Mycobacterium tuberculosis encode 28 and 13 different sigma factors, respectively, but SigA, the sole group 1 member in each species, is essential and is presumably responsible for expression of all or most housekeeping genes (4).…”

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confidence: 99%

Mutational Analysis of the Mycobacteriophage BPs Promoter PR Reveals Context-Dependent Sequences for Mycobacterial Gene Expression

Oldfield

Hatfull

2014

Journal of Bacteriology

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The P R promoter of mycobacteriophage BPs directs early lytic gene expression and is under the control of the BPs repressor, gp33. Reporter gene fusions showed that P R has modest activity in an extrachromosomal context but has activity that is barely detectable in an integrated context, even in the absence of its repressor. Mutational dissection of P R showed that it uses a canonical ؊10 hexamer recognized by SigA, and mutants with mutations to the sequence 5=-TATAMT had the greatest activities. It does not contain a 5=-TGN-extended ؊10 sequence, although mutants with mutations creating an extended ؊10 sequence had substantially increased promoter activity. Mutations in the ؊35 hexamer also influenced promoter activity but were strongly context dependent, and similar substitutions in the ؊35 hexamer differentially affected promoter activity, depending on the ؊10 and extended ؊10 motifs. This warrants caution in the construction of synthetic promoters or the bioinformatic prediction of promoter activity. Combinations of mutations throughout P R generated a calibrated series of promoters for expression of stably integrated recombinant genes in both Mycobacterium smegmatis and M. tuberculosis, with maximal promoter activity being more than 2-fold that of the strong hsp60 promoter.

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Sigma Factors: Key Molecules in Mycobacterium tuberculosis Physiology and Virulence

Cited by 45 publications

References 160 publications

The Alternative Sigma Factors SigE and SigB Are Involved in Tolerance and Persistence to Antitubercular Drugs

The Alternative Sigma Factors SigE and SigB Are Involved in Tolerance and Persistence to Antitubercular Drugs

Mycobacterium tuberculosis Serine/Threonine Protein Kinases

Mutational Analysis of the Mycobacteriophage BPs Promoter PR Reveals Context-Dependent Sequences for Mycobacterial Gene Expression

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