The Oxidation-sensing Regulator (MosR) Is a New Redox-dependent Transcription Factor in Mycobacterium tuberculosis

Brugarolas, Pedro; Movahedzadeh, Farahnaz; Wang, Yuehong; Zhang, Nan; Bartek, Iona L.; Gao, Yihe N.; Voskuil, Martin I.; Franzblau, Scott G.; He, Chuan

doi:10.1074/jbc.m112.388611

Cited by 64 publications

(69 citation statements)

References 53 publications

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“…Amongst these are the three biologically relevant MFR–DNA complex structures, namely, Bacillus subtilis OhrR (PDB code: 1Z9C, Z -score = 16.3) (1), Salmonella enterica SlyA (PDB code: 3Q5F, Z -score = 16.1) (5) and Mycobacterium tuberculosis MosR (PDB code: 4FX4, Z -score = 15.4) (18), which are broadly similar to the SCO3205-DNA complex (Supplementary Table S15 and Supplementary Figures S10 and S11), and, although the conformation of the DNA is somewhat variable, in none of the complexes is the DNA significantly bent.…”

Section: Resultsmentioning

confidence: 99%

“…Using reciprocal BLAST (16), likely orthologs of SCO3205 were predicted in 62 of these genomes. Subsequently, the upstream sequences of these orthologous genes were extracted and used as input to MEME (17), searching for recurring patterns of between 10 and 25 nt in length [from the biologically relevant crystal structures of MFR–DNA complexes (1,5,18), we expected footprints of ∼22 bp]. This analysis revealed two distinct yet homologous pseudopalindromic motifs upstream of the sco3205 coding sequence (Figure 1).…”

Section: Methodsmentioning

confidence: 99%

“…The 119 nt sequence of the intergenic region between sco3204 and sco3205 in the S. coelicolor genome was divided into a series of overlapping fragments using the program POOP (Supplementary Program 1 and Supplementary Figure S2). Overlaps are necessary to ensure that all potential binding sites are fully present in at least one of the fragments; based on the footprints observed in the known MFR–DNA structures, this was chosen as 22 nt (1,5,18). The choice of fragment length is a compromise between the lack of resolution if larger fragments are used, and the number of SPR experiments required if shorter fragments are used.…”

Section: Methodsmentioning

confidence: 99%

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Investigation of DNA sequence recognition by a streptomycete MarR family transcriptional regulator through surface plasmon resonance and X-ray crystallography

Stevenson

Assaad

Chandra

et al. 2013

Nucleic Acids Research

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Consistent with their complex lifestyles and rich secondary metabolite profiles, the genomes of streptomycetes encode a plethora of transcription factors, the vast majority of which are uncharacterized. Herein, we use Surface Plasmon Resonance (SPR) to identify and delineate putative operator sites for SCO3205, a MarR family transcriptional regulator from Streptomyces coelicolor that is well represented in sequenced actinomycete genomes. In particular, we use a novel SPR footprinting approach that exploits indirect ligand capture to vastly extend the lifetime of a standard streptavidin SPR chip. We define two operator sites upstream of sco3205 and a pseudopalindromic consensus sequence derived from these enables further potential operator sites to be identified in the S. coelicolor genome. We evaluate each of these through SPR and test the importance of the conserved bases within the consensus sequence. Informed by these results, we determine the crystal structure of a SCO3205-DNA complex at 2.8 Å resolution, enabling molecular level rationalization of the SPR data. Taken together, our observations support a DNA recognition mechanism involving both direct and indirect sequence readout.

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Section: Resultsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

See 1 more Smart Citation

Investigation of DNA sequence recognition by a streptomycete MarR family transcriptional regulator through surface plasmon resonance and X-ray crystallography

Stevenson

Assaad

Chandra

et al. 2013

Nucleic Acids Research

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“…For example, exposure to hydrogen peroxide or nitric oxide led to dissociation of MosR from DNA and subsequent upregulation of the putative oxidoreductase Rv1050 (38). Rv1404 was involved in Mtb's response to acid and hypoxia by up-regulating 10 genes, including two putative methyl transferases, Rv1403c and Rv1405c (39).…”

Section: Discussionmentioning

confidence: 99%

N -methylation of a bactericidal compound as a resistance mechanism in Mycobacterium tuberculosis

Warrier

Kapilashrami

Argyrou

et al. 2016

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

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The rising incidence of antimicrobial resistance (AMR) makes it imperative to understand the underlying mechanisms. Mycobacterium tuberculosis (Mtb) is the single leading cause of death from a bacterial pathogen and estimated to be the leading cause of death from AMR. A pyrido-benzimidazole, 14, was reported to have potent bactericidal activity against Mtb. Here, we isolated multiple Mtb clones resistant to 14. Each had mutations in the putative DNA-binding and dimerization domains of rv2887, a gene encoding a transcriptional repressor of the MarR family. The mutations in Rv2887 led to markedly increased expression of rv0560c. We characterized Rv0560c as an S-adenosyl-L-methionine-dependent methyltransferase that N-methylates 14, abolishing its mycobactericidal activity. An Mtb strain lacking rv0560c became resistant to 14 by mutating decaprenylphosphoryl-β-d-ribose 2-oxidase (DprE1), an essential enzyme in arabinogalactan synthesis; 14 proved to be a nanomolar inhibitor of DprE1, and methylation of 14 by Rv0560c abrogated this activity. Thus, 14 joins a growing list of DprE1 inhibitors that are potently mycobactericidal. Bacterial methylation of an antibacterial agent, 14, catalyzed by Rv0560c of Mtb, is a previously unreported mechanism of AMR.

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“…Enterococcus faecium (55), E. coli (56 -60), P. aeruginosa (20,21), and Mycobacterium tuberculosis (61). Several redox-sensitive regulatory proteins act as major regulators of bacteria adaptability to oxidative stress or antibiotic stress and impact bacterial virulence (19 -22, 55).…”

Section: Discussionmentioning

confidence: 99%

Oxidation-sensing Regulator AbfR Regulates Oxidative Stress Responses, Bacterial Aggregation, and Biofilm Formation in Staphylococcus epidermidis

Liu

Sun

et al. 2013

Journal of Biological Chemistry

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Background: Staphylococcus epidermidis senses and responds to oxidative stress through an unknown mechanism. Results: The paper describes AbfR, the first oxidation sensor of S. epidermidis. Conclusion: AbfR plays key roles in oxidative stress responses, bacterial aggregation, and biofilm formation in S. epidermidis. Significance: Oxidative stress signals S. epidermidis to modulate key virulence properties through AbfR.

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The Oxidation-sensing Regulator (MosR) Is a New Redox-dependent Transcription Factor in Mycobacterium tuberculosis

Cited by 64 publications

References 53 publications

Investigation of DNA sequence recognition by a streptomycete MarR family transcriptional regulator through surface plasmon resonance and X-ray crystallography

Investigation of DNA sequence recognition by a streptomycete MarR family transcriptional regulator through surface plasmon resonance and X-ray crystallography

N -methylation of a bactericidal compound as a resistance mechanism in Mycobacterium tuberculosis

Oxidation-sensing Regulator AbfR Regulates Oxidative Stress Responses, Bacterial Aggregation, and Biofilm Formation in Staphylococcus epidermidis

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