The Mycobacterial Transcriptional Regulator whiB7 Gene Links Redox Homeostasis and Intrinsic Antibiotic Resistance

Burian, Ján; Ramón-García, Santiago; Sweet, Gaye; Gómez‐Velasco, Anaximandro; Av‐Gay, Yossef; Thompson, Charles J.

doi:10.1074/jbc.m111.302588

Cited by 107 publications

(194 citation statements)

References 44 publications

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“…Finally, for 1 of the 38 resistant clones without a mutation in atpE and atpB, selected on 0.5 mg/liter of TMC207, the sequences of the genes encoding the complete ATP synthase operon (F O and F 1 domains) were all found to be wild type compared to the reference sequence from H37Rv, highlighting that mechanisms not related to mutations in the ATP synthase operon can also contribute to resistance to TMC207 in M. tuberculosis and M. abscessus. Alternative hypotheses can be formulated to explain the resistance observed in the nonmutated clones, which include inactivation of the drug (a mechanism that cannot be excluded) or, alternatively, a change in pleiotropic transcriptional regulators affecting the intrinsic resistance of mycobacteria, such as WhiB7, affecting cellular metabolism (6). Further investigations about the possible other mechanisms of resistance to TMC207 are under way to elucidate this point.…”

Section: Discussionmentioning

confidence: 99%

New Mutations in the Mycobacterial ATP Synthase: New Insights into the Binding of the Diarylquinoline TMC207 to the ATP Synthase C-Ring Structure

Segala

Sougakoff

Nevejans-Chauffour

et al. 2012

Antimicrob Agents Chemother

109

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TMC207 is a new antituberculous drug belonging to the diarylquinoline class which very efficiently inhibits the ATP synthase of mycobacteria such as Mycobacterium tuberculosis, one of the most important pathogens in the world. In order to map the amino acid residues involved in the binding of the drug, we have selected in vitro TMC207-resistant mutants from M. tuberculosis and diverse atypical mycobacteria. Six distinct mutations, Asp28¡Gly, Asp28¡Ala, Leu59¡Val, Glu61¡Asp, Ala63¡Pro, and Ile66¡Met, have been identified in the subunit c forming a C ring in the ATP synthase. They were studied by evaluating the levels of resistance that they confer in the selected clones and by using an isogenic complementation system in Mycobacterium smegmatis. The rates of increase of TMC207 MIC values (8-to 133-fold) were interpreted by constructing by homology modeling a structure of the mycobacterial C ring which was used for docking simulations with TMC207. Our results suggest that the residues found to be mutated in the resistant clones, together with a tyrosine specifically conserved at position 64 in mycobacteria, define a cleft located between two adjacent c subunits in the C ring. This cleft, which encompasses the proton-binding site (Glu61), is well fitted to bind TMC207 at the level of the bromoquinoline moiety, with the drug being anchored by several ionic, hydrogen, and halogen bonds with residues Glu61, Tyr64, and Asp28, respectively. These data shed light on the molecular interactions allowing TMC207 to bind specifically and efficiently at the level of the proton-binding site of the mycobacterial C ring.

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Section: Discussionmentioning

confidence: 99%

New Mutations in the Mycobacterial ATP Synthase: New Insights into the Binding of the Diarylquinoline TMC207 to the ATP Synthase C-Ring Structure

Segala

Sougakoff

Nevejans-Chauffour

et al. 2012

Antimicrob Agents Chemother

109

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“…Although this seems a reasonable assumption, it has not been confirmed experimentally. Thus, it remains possible that a transcription factor other than SigA is involved in promoting transcription from this Beijing-specific promoter region, or if SigA is involved, it may be doing so in the presence of an additional transcriptional activator (56).…”

Section: Fig 6 the Dost Defect In Beijing Isolates Has No Impact On Tmentioning

confidence: 99%

“…This is also interesting in light of the precedent in the literature that implicates the WhiB3 and WhiB7 transcription factors in modifying M. tuberculosis drug susceptibility. Like DosR, both of these transcription factors are known to regulate the cellular response to redox stress (56,68).…”

Section: Fig 6 the Dost Defect In Beijing Isolates Has No Impact On Tmentioning

confidence: 99%

Unique Regulation of the DosR Regulon in the Beijing Lineage of Mycobacterium tuberculosis

et al. 2017

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The DosR regulon, a set of 48 genes normally expressed in Mycobacterium tuberculosis under conditions that inhibit aerobic respiration, is controlled via the DosR-DosS/DosT two-component system. While the regulon requires induction in most M. tuberculosis isolates, for members of the Beijing lineage, its expression is uncoupled from the need for signaling. In our attempts to understand the mechanistic basis for this uncoupling in the Beijing background, we previously reported the identification of two synonymous single-nucleotide polymorphisms (SNPs) within the adjacent Rv3134c gene. In the present study, we have interrogated the impact of these SNPs on dosR expression in wild-type strains, as well as a range of dosRdosS-dosT mutants, for both Beijing and non-Beijing M. tuberculosis backgrounds. In this manner, we have unequivocally determined that the C601T dosR promoter SNP is the sole requirement for the dramatic shift in the pattern of DosR regulon expression seen in this globally important lineage. Interestingly, we also show that DosT is completely nonfunctional within these strains. Thus, a complex series of evolutionary steps has led to the present-day Beijing DosR phenotype that, in turn, potentially confers a fitness advantage in the face of some form of host-associated selective pressure.IMPORTANCE Mycobacterium tuberculosis strains of the Beijing lineage have been described as being of enhanced virulence compared to other lineages, and in certain regions, they are associated with the dramatic spread of multidrug-resistant tuberculosis (TB). In terms of trying to understand the functional basis for these broad epidemiological phenomena, it is interesting that, in contrast to the other major lineages, the Beijing strains all constitutively overexpress members of the DosR regulon. Here, we identify the mutational events that led to the evolution of this unique phenotype. In addition, our work highlights the fact that important phenotypic differences exist between distinct M. tuberculosis lineages, with the potential to impact the efficacy of diagnosis, vaccination, and treatment programs.KEYWORDS Tuberculosis, DosR regulon, strain variation, evolution, Mycobacterium tuberculosis D espite being an ancient disease, human tuberculosis (TB) resulting from infection with Mycobacterium tuberculosis still remains a leading cause of death worldwide as a consequence of multiple contributing factors, including drug resistance, HIV coinfection, and inadequate access to high-quality health care (1). Furthermore, recent evidence suggests that the level of genetic diversity that exists among distinct M. tuberculosis isolates was previously underestimated and has the potential to impact pathogenicity, as well as to limit the effectiveness of current diagnostic and therapeutic interventions (2-4).

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“…While the regulatory mechanisms governing these gene expression changes have not been completely described, there is some evidence for transcriptional regulation of EPs. In this regard, it has been shown that WhiB7, a redox-sensitive transcriptional activator, plays an important role in mediating intrinsic drug resistance in mycobacteria, in some cases through direct regulation of EPs (147)(148)(149). Similarly, resistance to INH has been associated with the IniBIniA-IniC efflux system (Table 1), which is regulated by the MtrAB two-component system (150), and the mmr-encoded EP is regulated by a TetR-type repressor (151).…”

Section: Energy Metabolism and Drug Effluxmentioning

confidence: 99%

Energy Metabolism and Drug Efflux in Mycobacterium tuberculosis

Black

Warren

Louw

et al. 2014

Antimicrob Agents Chemother

117

102

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cThe inherent drug susceptibility of microorganisms is determined by multiple factors, including growth state, the rate of drug diffusion into and out of the cell, and the intrinsic vulnerability of drug targets with regard to the corresponding antimicrobial agent. Mycobacterium tuberculosis, the causative agent of tuberculosis (TB), remains a significant source of global morbidity and mortality, further exacerbated by its ability to readily evolve drug resistance. It is well accepted that drug resistance in M. tuberculosis is driven by the acquisition of chromosomal mutations in genes encoding drug targets/promoter regions; however, a comprehensive description of the molecular mechanisms that fuel drug resistance in the clinical setting is currently lacking. In this context, there is a growing body of evidence suggesting that active extrusion of drugs from the cell is critical for drug tolerance. M. tuberculosis encodes representatives of a diverse range of multidrug transporters, many of which are dependent on the proton motive force (PMF) or the availability of ATP. This suggests that energy metabolism and ATP production through the PMF, which is established by the electron transport chain (ETC), are critical in determining the drug susceptibility of M. tuberculosis. In this review, we detail advances in the study of the mycobacterial ETC and highlight drugs that target various components of the ETC. We provide an overview of some of the efflux pumps present in M. tuberculosis and their association, if any, with drug transport and concomitant effects on drug resistance. The implications of inhibiting drug extrusion, through the use of efflux pump inhibitors, are also discussed.

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The Mycobacterial Transcriptional Regulator whiB7 Gene Links Redox Homeostasis and Intrinsic Antibiotic Resistance

Cited by 107 publications

References 44 publications

New Mutations in the Mycobacterial ATP Synthase: New Insights into the Binding of the Diarylquinoline TMC207 to the ATP Synthase C-Ring Structure

New Mutations in the Mycobacterial ATP Synthase: New Insights into the Binding of the Diarylquinoline TMC207 to the ATP Synthase C-Ring Structure

Unique Regulation of the DosR Regulon in the Beijing Lineage of Mycobacterium tuberculosis

Energy Metabolism and Drug Efflux in Mycobacterium tuberculosis

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