Imperial College London

ProfessorSivarameshWigneshweraraj

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

71 results found

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, Wigneshweraraj Set al., 2017, Phenotypic consequences of RNA polymerase dysregulation in Escherichia coli., Nucleic Acids Res

Many bacterial adaptive responses to changes in growth conditions due to biotic and abiotic factors involve reprogramming of gene expression at the transcription level. The bacterial RNA polymerase (RNAP), which catalyzes transcription, can thus be considered as the major mediator of cellular adaptive strategies. But how do bacteria respond if a stress factor directly compromises the activity of the RNAP? We used a phage-derived small protein to specifically perturb bacterial RNAP activity in exponentially growing Escherichia coli. Using cytological profiling, tracking RNAP behavior at single-molecule level and transcriptome analysis, we reveal that adaptation to conditions that directly perturb bacterial RNAP performance can result in a biphasic growth behavior and thereby confer the 'adapted' bacterial cells an enhanced ability to tolerate diverse antibacterial stresses. The results imply that while synthetic transcriptional rewiring may confer bacteria with the intended desirable properties, such approaches may also collaterally allow them to acquire undesirable traits.

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

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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

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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

Shadrin A, Sheppard C, Severinov K, Matthews S, Wigneshweraraj Set al., 2012, Substitutions in the Escherichia coli RNA polymerase inhibitor T7 Gp2 that allow inhibition of transcription when the primary interaction interface between Gp2 and RNA polymerase becomes compromised, MICROBIOLOGY-SGM, Vol: 158, Pages: 2753-2764, ISSN: 1350-0872

JOURNAL ARTICLE

Jovanovic M, Burrows PC, Bose D, Camara B, Wiesler S, Zhang X, Wigneshweraraj S, Weinzierl ROJ, Buck Met al., 2011, Activity Map of the Escherichia coli RNA Polymerase Bridge Helix, JOURNAL OF BIOLOGICAL CHEMISTRY, Vol: 286, Pages: 14469-14479, ISSN: 0021-9258

JOURNAL ARTICLE

Mekler V, Minakhin L, Sheppard C, Wigneshweraraj S, Severinov Ket al., 2011, Molecular Mechanism of Transcription Inhibition by Phage T7 gp2 Protein, JOURNAL OF MOLECULAR BIOLOGY, Vol: 413, Pages: 1016-1027, ISSN: 0022-2836

JOURNAL ARTICLE

Reynolds J, Wigneshweraraj S, 2011, Molecular Insights into the Control of Transcription Initiation at the Staphylococcus aureus agr operon, JOURNAL OF MOLECULAR BIOLOGY, Vol: 412, Pages: 862-881, ISSN: 0022-2836

JOURNAL ARTICLE

Sheppard C, Camara B, Shadrin A, Akulenko N, Liu M, Baldwin G, Severinov K, Cota E, Matthews S, Wigneshweraraj SRet al., 2011, Reprint of: Inhibition of Escherichia coli RNAp by T7 Gp2 protein: Role of Negatively Charged Strip of Amino Acid Residues in Gp2, JOURNAL OF MOLECULAR BIOLOGY, Vol: 412, Pages: 832-841, ISSN: 0022-2836

JOURNAL ARTICLE

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