Imperial College London

Professor Ramesh Wigneshweraraj

Faculty of MedicineDepartment of Medicine

Professor of Molecular Microbiology
 
 
 
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Contact

 

+44 (0)20 7594 1867s.r.wig

 
 
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Location

 

4.40BFlowers buildingSouth Kensington Campus

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Summary

 

Publications

Publication Type
Year
to

76 results found

Duchi D, Gryte K, Robb NC, Morichaud Z, Sheppard C, Brodolin K, Wigneshweraraj S, Kapanidis ANet al., 2018, Conformational heterogeneity and bubble dynamics in single bacterial transcription initiation complexes, NUCLEIC ACIDS RESEARCH, Vol: 46, Pages: 677-688, ISSN: 0305-1048

JOURNAL ARTICLE

Krishna A, Holden MTG, Peacock SJ, Edwards AM, Wigneshweraraj Set al., 2018, Naturally occurring polymorphisms in the virulence regulator Rsp modulate Staphylococcus aureus survival in blood and antibiotic susceptibility., Microbiology

Nasal colonization by the pathogen Staphylococcus aureus is a risk factor for subsequent infection. Loss of function mutations in the gene encoding the virulence regulator Rsp are associated with the transition of S. aureus from a colonizing isolate to one that causes bacteraemia. Here, we report the identification of several novel activity-altering mutations in rsp detected in clinical isolates, including for the first time, mutations that enhance agr operon activity. We assessed how these mutations affected infection-relevant phenotypes and found loss and enhancement of function mutations to have contrasting effects on S. aureus survival in blood and antibiotic susceptibility. These findings add to the growing body of evidence that suggests S. aureus 'trades off' virulence for the acquisition of traits that benefit survival in the host, and indicates that infection severity and treatment options can be significantly affected by mutations in the virulence regulator rsp.

JOURNAL ARTICLE

Liu B, Wang Z, Lan L, Yang Q, Zhang P, Shi L, Lang Y, Tabib-Salazar A, Wigneshweraraj S, Zhang J, Wang Y, Tang Y, Matthews S, Zhang Xet al., 2018, A Rapid Colorimetric Method to Visualize Protein Interactions, CHEMISTRY-A EUROPEAN JOURNAL, Vol: 24, Pages: 6727-6731, ISSN: 0947-6539

JOURNAL ARTICLE

Switzer A, Evangelopoulos D, Figueira R, de Carvalho LPS, Brown DR, Wigneshweraraj Set al., 2018, A novel regulatory factor affecting the transcription of methionine biosynthesis genes in Escherichia coli experiencing sustained nitrogen starvation., Microbiology

The initial adaptive transcriptional response to nitrogen (N) starvation in Escherichia coli involves large-scale alterations to the transcriptome mediated by the transcriptional activator, NtrC. One of these NtrC-activated genes is yeaG, which encodes a conserved bacterial kinase. Although it is known that YeaG is required for optimal survival under sustained N starvation, the molecular basis by which YeaG benefits N starved E. coli remains elusive. By combining transcriptomics with targeted metabolomics analyses, we demonstrate that the methionine biosynthesis pathway becomes transcriptionally dysregulated in ΔyeaG bacteria experiencing sustained N starvation. It appears the ability of MetJ, the master transcriptional repressor of methionine biosynthesis genes, to effectively repress transcription of genes under its control is compromised in ΔyeaG bacteria under sustained N starvation, resulting in transcriptional derepression of MetJ-regulated genes. Although the aberrant biosynthesis does not appear to be a contributing factor for the compromised viability of ΔyeaG bacteria experiencing sustained N starvation, this study identifies YeaG as a novel regulatory factor in E. coli affecting the transcription of methionine biosynthesis genes under sustained N starvation.

JOURNAL ARTICLE

Tabib-Salazar A, Liu B, Barker D, Burchell L, Qimron U, Matthews SJ, Wigneshwerararj Set al., 2018, T7 phage factor required for managing RpoS in Escherichia coli, PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, Vol: 115, Pages: E5353-E5362, ISSN: 0027-8424

JOURNAL ARTICLE

Pader V, Hakim S, Painter KL, Wigneshweraraj S, Clarke TB, Edwards AMet al., 2017, Staphylococcus aureus inactivates daptomycin by releasing membrane phospholipids, NATURE MICROBIOLOGY, Vol: 2, ISSN: 2058-5276

JOURNAL ARTICLE

Sarkar P, Switzer A, Peters C, Pogliano J, Wigneshwerarar Set al., 2017, Phenotypic consequences of RNA polymerase dysregulation in Escherichia coli, NUCLEIC ACIDS RESEARCH, Vol: 45, Pages: 11131-11143, ISSN: 0305-1048

JOURNAL ARTICLE

Tabib-Salazar A, Liu B, Shadrin A, Burchell L, Wang Z, Wang Z, Goren MG, Yosef I, Qimron U, Severinov K, Matthews SJ, Wigneshweraraj Set al., 2017, Full shut-off of Escherichia coli RNA-polymerase by T7 phage requires a small phage-encoded DNA-binding protein, NUCLEIC ACIDS RESEARCH, Vol: 45, Pages: 7697-7707, ISSN: 0305-1048

JOURNAL ARTICLE

du Plessis J, Cloete R, Burchell L, Sarkar P, Warren RM, Christoffels A, Wigneshweraraj S, Sampson SLet al., 2017, Exploring the potential of T7 bacteriophage protein Gp2 as a novel inhibitor of mycobacterial RNA polymerase, TUBERCULOSIS, Vol: 106, Pages: 82-90, ISSN: 1472-9792

JOURNAL ARTICLE

Brown DR, Sheppard CM, Burchell L, Matthews S, Wigneshweraraj Set al., 2016, The Xp10 Bacteriophage Protein P7 Inhibits Transcription by the Major and Major Variant Forms of the Host RNA Polymerase via a Common Mechanism, JOURNAL OF MOLECULAR BIOLOGY, Vol: 428, Pages: 3911-3919, ISSN: 0022-2836

JOURNAL ARTICLE

Figueira R, Brown DR, Ferreira D, Eldridge MJG, Burchell L, Pan Z, Helaine S, Wigneshweraraj Set al., 2015, Adaptation to sustained nitrogen starvation by Escherichia coli requires the eukaryote-like serine/threonine kinase YeaG, SCIENTIFIC REPORTS, Vol: 5, ISSN: 2045-2322

JOURNAL ARTICLE

Thompson CC, Griffiths C, Nicod SS, Lowden NM, Wigneshweraraj S, Fisher DJ, McClure MOet al., 2015, The Rsb Phosphoregulatory Network Controls Availability of the Primary Sigma Factor in Chlamydia trachomatis and Influences the Kinetics of Growth and Development, PLOS PATHOGENS, Vol: 11, ISSN: 1553-7366

JOURNAL ARTICLE

Brown DR, Barton G, Pan Z, Buck M, Wigneshweraraj Set al., 2014, Nitrogen stress response and stringent response are coupled in Escherichia coli, NATURE COMMUNICATIONS, Vol: 5, ISSN: 2041-1723

JOURNAL ARTICLE

Brown DR, Barton G, Pan Z, Buck M, Wigneshweraraj Set al., 2014, Combinatorial stress responses: direct coupling of two major stress responses in Escherichia coli., Microb Cell, Vol: 1, Pages: 315-317, ISSN: 2311-2638

Nitrogen is an essential element for all life, and this is no different for the bacterial cell. Numerous cellular macromolecules contain nitrogen, including proteins, nucleic acids and cell wall components. In Escherichia coli and related bacteria, the nitrogen stress (Ntr) response allows cells to rapidly sense and adapt to nitrogen limitation by scavenging for alternative nitrogen sources through the transcriptional activation of transport systems and catabolic and biosynthetic operons by the global transcriptional regulator NtrC. Nitrogen-starved bacterial cells also synthesize the (p)ppGpp effector molecules of a second global bacterial stress response - the stringent response. Recently, we showed that the transcription of relA, the gene which encodes the major (p)ppGpp synthetase in E. coli, is activated by NtrC during nitrogen starvation. Our results revealed that in E. coli and related bacteria, NtrC functions in combinatorial stress and serves to couple two major stress responses, the Ntr response and stringent response.

JOURNAL ARTICLE

Liu B, Shadrin A, Sheppard C, Mekler V, Xu Y, Severinov K, Matthews S, Wigneshweraraj Set al., 2014, A bacteriophage transcription regulator inhibits bacterial transcription initiation by Sigma-factor displacement, NUCLEIC ACIDS RESEARCH, Vol: 42, Pages: 4294-4305, ISSN: 0305-1048

JOURNAL ARTICLE

Liu B, Shadrin A, Sheppard C, Mekler V, Xu Y, Severinov K, Matthews S, Wigneshweraraj Set al., 2014, The sabotage of the bacterial transcription machinery by a small bacteriophage protein., Bacteriophage, Vol: 4, ISSN: 2159-7073

Many bacteriophages produce small proteins that specifically interfere with the bacterial host transcription machinery and thus contribute to the acquisition of the bacterial cell by the bacteriophage. We recently described how a small protein, called P7, produced by the Xp10 bacteriophage inhibits bacterial transcription initiation by causing the dissociation of the promoter specificity sigma factor subunit from the host RNA polymerase holoenzyme. In this addendum to the original publication, we present the highlights of that research.

JOURNAL ARTICLE

Nicod SS, Weinzierl RO, Burchell L, Escalera-Maurer A, James EH, Wigneshweraraj Set al., 2014, Systematic mutational analysis of the LytTR DNA binding domain of Staphylococcus aureus virulence gene transcription factor AgrA., Nucleic Acids Research, Vol: 42, Pages: 12523-12536, ISSN: 1362-4962

Most DNA-binding bacterial transcription factors contact DNA through a recognition α-helix in their DNA-binding domains. An emerging class of DNA-binding transcription factors, predominantly found in pathogenic bacteria interact with the DNA via a relatively novel type of DNA-binding domain, called the LytTR domain, which mainly comprises β strands. Even though the crystal structure of the LytTR domain of the virulence gene transcription factor AgrA from Staphylococcus aureus bound to its cognate DNA sequence is available, the contribution of specific amino acid residues in the LytTR domain of AgrA to transcription activation remains elusive. Here, for the first time, we have systematically investigated the role of amino acid residues in transcription activation in a LytTR domain-containing transcription factor. Our analysis, which involves in vivo and in vitro analyses and molecular dynamics simulations of S. aureus AgrA identifies a highly conserved tyrosine residue, Y229, as a major amino acid determinant for maximal activation of transcription by AgrA and provides novel insights into structure-function relationships in S. aureus AgrA.

JOURNAL ARTICLE

Pader V, James EH, Painter KL, Wigneshweraraj S, Edwards AMet al., 2014, The Agr Quorum-Sensing System Regulates Fibronectin Binding but Not Hemolysis in the Absence of a Functional Electron Transport Chain, INFECTION AND IMMUNITY, Vol: 82, Pages: 4337-4347, ISSN: 0019-9567

JOURNAL ARTICLE

Painter KL, Krishna A, Wigneshweraraj S, Edwards AMet al., 2014, What role does the quorum-sensing accessory gene regulator system play during Staphylococcus aureus bacteremia?, TRENDS IN MICROBIOLOGY, Vol: 22, Pages: 676-685, ISSN: 0966-842X

JOURNAL ARTICLE

Sharma A, Leach RN, Gell C, Zhang N, Burrows PC, Shepherd DA, Wigneshweraraj S, Smith DA, Zhang X, Buck M, Stockley PG, Tuma Ret al., 2014, Domain movements of the enhancer-dependent sigma factor drive DNA delivery into the RNA polymerase active site: insights from single molecule studies, NUCLEIC ACIDS RESEARCH, Vol: 42, Pages: 5177-5190, ISSN: 0305-1048

JOURNAL ARTICLE

Thomas MS, Wigneshweraraj S, 2014, Regulation of virulence gene expression, VIRULENCE, Vol: 5, Pages: 832-834, ISSN: 2150-5594

JOURNAL ARTICLE

Bae B, Davis E, Brown D, Campbell EA, Wigneshweraraj S, Darst SAet al., 2013, Phage T7 Gp2 inhibition of Escherichia coli RNA polymerase involves misappropriation of sigma(70) domain 1.1, PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, Vol: 110, Pages: 19772-19777, ISSN: 0027-8424

JOURNAL ARTICLE

James EH, Edwards AM, Wigneshweraraj S, 2013, Transcriptional downregulation of agr expression in Staphylococcus aureus during growth in human serum can be overcome by constitutively active mutant forms of the sensor kinase AgrC, FEMS MICROBIOLOGY LETTERS, Vol: 349, Pages: 153-162, ISSN: 0378-1097

JOURNAL ARTICLE

Schumacher J, Behrends V, Pan Z, Brown DR, Heydenreich F, Lewis MR, Bennett MH, Razzaghi B, Komorowski M, Barahona M, Stumpf MPH, Wigneshweraraj S, Bundy JG, Buck Met al., 2013, Nitrogen and Carbon Status Are Integrated at the Transcriptional Level by the Nitrogen Regulator NtrC In Vivo, MBIO, Vol: 4, ISSN: 2150-7511

JOURNAL ARTICLE

Shadrin A, Sheppard C, Savalia D, Severinov K, Wigneshweraraj Set al., 2013, Overexpression of Escherichia coli udk mimics the absence of T7 Gp2 function and thereby abrogates successful infection by T7 phage, MICROBIOLOGY-SGM, Vol: 159, Pages: 269-274, ISSN: 1350-0872

JOURNAL ARTICLE

Sheppard C, James E, Barton G, Matthews S, Severinov K, Wigneshweraraj Set al., 2013, A non-bacterial transcription factor inhibits bacterial transcription by a multipronged mechanism, RNA BIOLOGY, Vol: 10, Pages: 495-501, ISSN: 1547-6286

JOURNAL ARTICLE

Chakraborty A, Wang D, Ebright YW, Korlann Y, Kortkhonjia E, Kim T, Chowdhury S, Wigneshweraraj S, Irschik H, Jansen R, Nixon BT, Knight J, Weiss S, Ebright RHet al., 2012, Opening and Closing of the Bacterial RNA Polymerase Clamp, SCIENCE, Vol: 337, Pages: 591-595, ISSN: 0036-8075

JOURNAL ARTICLE

Drennan A, Kraemer M, Capp M, Gries T, Ruff E, Sheppard C, Wigneshweraraj S, Artsimovitch I, Record MTet al., 2012, Key Roles of the Downstream Mobile Jaw of Escherichia coli RNA Polymerase in Transcription Initiation, BIOCHEMISTRY, Vol: 51, Pages: 9447-9459, ISSN: 0006-2960

JOURNAL ARTICLE

Drennan A, Saecker R, Heitkamp S, Capp M, Kraemer M, Bellissimo D, Gries T, Ruff E, Sheppard C, Wigneshweraraj S, Artsimovitch I, Record MTet al., 2012, E. Coli RNA Polymerase: A Molecular DNA Opening Machine, BIOPHYSICAL JOURNAL, Vol: 102, Pages: 286A-286A, ISSN: 0006-3495

JOURNAL ARTICLE

James E, Liu M, Sheppard C, Mekler V, Camara B, Liu B, Simpson P, Cota E, Severinov K, Matthews S, Wigneshweraraj Set al., 2012, Structural and Mechanistic Basis for the Inhibition of Escherichia coli RNA Polymerase by T7 Gp2, MOLECULAR CELL, Vol: 47, Pages: 755-766, ISSN: 1097-2765

JOURNAL ARTICLE

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