The RNA polymerase‐binding protein RbpA confers basal levels of rifampicin resistance on <i>Streptomyces coelicolor</i>

Newell, Katy V.; Thomas, Derek P.; Brekasis, Dimitris; Paget, Mark S. B.

doi:10.1111/j.1365-2958.2006.05116.x

Cited by 63 publications

(80 citation statements)

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“…Both RbpA and CarD are essential transcription activators in Mtb (10,12). CarD is associated with essentially all σ A promoters in Mycobacterium smegmatis in vivo (13), and results suggest that RbpA also likely functions at most, if not all, housekeeping σ-dependent promoters in vivo (11,15). Therefore, it seems likely that RbpA and CarD may function simultaneously on the same RNAP-promoter complexes.…”

Section: Discussionmentioning

confidence: 93%

“…Recently, it has emerged that the regulation of transcription initiation in the Actinobacteria phylum, which includes major pathogens, such as Mycobacterium tuberculosis (Mtb), and antibiotic producers, such as Streptomyces spp., is distinct from the Eco system by the dependence on two initiation factors, CarD and RbpA, neither of which is found in Eco (10)(11)(12).…”

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confidence: 99%

“…RbpA is found in almost all Actinobacteria and like CarD, essential for growth in Mtb (11,12). Compared with CarD, much less is known about the RbpA structural mechanism.…”

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confidence: 99%

“…RbpA was originally discovered in Streptomyces coelicolor (Sco), where it is a major component of RNAP holoenzyme (11). RbpA is found in almost all Actinobacteria and like CarD, essential for growth in Mtb (11,12).…”

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confidence: 99%

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Structural, functional, and genetic analyses of the actinobacterial transcription factor RbpA

Hubin

Tabib-Salazar

Humphrey

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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Gene expression is highly regulated at the step of transcription initiation, and transcription activators play a critical role in this process. RbpA, an actinobacterial transcription activator that is essential in Mycobacterium tuberculosis (Mtb), binds selectively to group 1 and certain group 2 σ-factors. To delineate the molecular mechanism of RbpA, we show that the Mtb RbpA σ-interacting domain (SID) and basic linker are sufficient for transcription activation. We also present the crystal structure of the Mtb RbpA-SID in complex with domain 2 of the housekeeping σ-factor, σ A . The structure explains the basis of σ-selectivity by RbpA, showing that RbpA interacts with conserved regions of σ A as well as the nonconserved region (NCR), which is present only in housekeeping σ-factors. Thus, the structure is the first, to our knowledge, to show a protein interacting with the NCR of a σ-factor. We confirm the basis of selectivity and the observed interactions using mutagenesis and functional studies. In addition, the structure allows for a model of the RbpA-SID in the context of a transcription initiation complex. Unexpectedly, the structural modeling suggests that RbpA contacts the promoter DNA, and we present in vivo and in vitro studies supporting this finding. Our combined data lead to a better understanding of the mechanism of RbpA function as a transcription activator.RbpA | X-ray crystallography | transcription | actinobacteria | mycobacteria

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Section: Discussionmentioning

confidence: 93%

mentioning

confidence: 99%

“…RbpA is found in almost all Actinobacteria and like CarD, essential for growth in Mtb (11,12). Compared with CarD, much less is known about the RbpA structural mechanism.…”

mentioning

confidence: 99%

mentioning

confidence: 99%

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Structural, functional, and genetic analyses of the actinobacterial transcription factor RbpA

Hubin

Tabib-Salazar

Humphrey

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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“…Orthologues of this protein are only found in actinomycetes. Recently, it was shown that this gene is also induced by rifamicin, and that RbpA is able to stimulate the expression of the rRNA operon even in the presence of rifamicin, conferring a basal level of resistance to this drug (Newell et al, 2006). In M. tuberculosis, Rv2050 was shown to be under the transcriptional control of SigH (SigR orthologue) and upregulated after heat shock and disulfide stress (Manganelli et al, 2002).…”

Section: Resultsmentioning

confidence: 99%

Global transcriptional response to vancomycin in Mycobacterium tuberculosis

et al. 2009

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In order to gain additional understanding of the physiological mechanisms used by bacteria to maintain surface homeostasis and to identify potential targets for new antibacterial drugs, we analysed the variation of the Mycobacterium tuberculosis transcriptional profile in response to inhibitory and subinhibitory concentrations of vancomycin. Our analysis identified 153 genes differentially regulated after exposing bacteria to a concentration of the drug ten times higher than the MIC, and 141 genes differentially expressed when bacteria were growing in a concentration of the drug eightfold lower than the MIC. Hierarchical clustering analysis indicated that the response to these different conditions is different, although with some overlap. This approach allowed us to identify several genes whose products could be involved in the protection from antibiotic stress targeting the envelope and help to confer the basal level of M. tuberculosis resistance to antibacterial drugs, such as Rv2623 (UspA-like), Rv0116c, PE20-PPE31, PspA and proteins related to toxin-antitoxin systems. Moreover, we also demonstrated that the alternative sigma factor s E confers basal resistance to vancomycin, once again underlining its importance in the physiology of the mycobacterial surface stress response. INTRODUCTIONMycobacterium tuberculosis remains one of the world's most prevalent and serious pathogens. It is estimated that every year 2 million people die as a direct result of tuberculosis and that there is a reservoir of 2 billion cryptically infected people (Dye et al., 1999). Of these asymptomatic carriers, around 5 % will develop active disease at some stage in their lives and in doing so will contribute to the ongoing transmission of infection (Raviglione, 2003). The recent emergence of multidrugresistant (MDR) and extensively drug-resistant (XDR-TB) strains (Gandhi et al., 2006) has raised the importance of searching for alternative targets to develop new antimycobacterial drugs.Due to the importance of its physiological role and its difference from the eukaryotic cell surface, the bacterial cell wall is one of the best candidates in the search for new drug targets. A large number of antibacterial drugs currently in use are directed against surface components or metabolic pathways that are involved in their synthesis. For example, b-lactams, cephalosporins, glycopeptides, phosphomycin, bacitracin and cycloserine inhibit peptidoglycan biosynthesis, while polymyxin interferes with the cell-membrane structure. Moreover, compounds such as isoniazid, pyrazinamide, ethambutol and ethionamide target typical components of the mycobacterial cell surface. In spite of a good knowledge of the chemical composition of the mycobacterial surface, not much is known about its organization and physiology (Barry, 2001). The recent demonstration of the presence of an outer membrane will surely boost research in this field (Hoffmann et al., 2008;Zuber et al., 2008).One strategy to study bacterial surface physiology is to characterize the variation o...

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Heat‐killed Mycolicibacterium aurum Aogashima: An environmental nonpathogenic actinobacteria under development as a safe novel food ingredient

Nouioui

Dye²

2021

Food Science & Nutrition

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The RNA polymerase‐binding protein RbpA confers basal levels of rifampicin resistance on Streptomyces coelicolor

Cited by 63 publications

References 50 publications

Structural, functional, and genetic analyses of the actinobacterial transcription factor RbpA

Structural, functional, and genetic analyses of the actinobacterial transcription factor RbpA

Global transcriptional response to vancomycin in Mycobacterium tuberculosis

Heat‐killed Mycolicibacterium aurum Aogashima: An environmental nonpathogenic actinobacteria under development as a safe novel food ingredient

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