Yr Athro Eshwar Mahenthiralingam

Professor

: mahenthiralingame@cardiff.ac.uk
: +44 (0)29 2087 5875
Fax:: +44 (0)29 2087 4305
: Cardiff School of Biosciences, Main Building, Museum Avenue, Cardiff, CF10 3AT, Adeilad Syr Martin Evans, Rhodfa'r Amgueddfa, Caerdydd, CF10 3AX

: Ar gael fel goruchwyliwr ôl-raddedig

Research overview

My group has studied the pathogenesis and ecology of bacterial opportunistic pathogens, ranging from Pseudomonas aeruginosa to mycobacteria, with a major focus on Burkholderia cepacia complex bacteria. Pseudomonas and Burkholderia bacteria cause devastating infections in people with cystic fibrosis and we have used molecular biology and genomic approaches to track their ability to spread between patients, resist killing by antibiotics and cause lung disease. Since both these bacteria are also important in the natural environment, we have also studied several aspects of their ecology. By understanding the complete biology of opportunistic bacterial pathogens in this way we hope to develop strategies to both treat human infection and also harness their considerable biotechnological potential. For example, our recent discovery that Burkholderia bacteria can produce novel polyketide antibiotics that target multidrug resistant bacterial infections is very exciting.

We are pleased to announced the forthcoming publication of a second book on Burkholderia bacteria: "Burkholderia: from genomes to function" which can be previewed at Horizon Press (http://www.horizonpress.com/burk2).

The book was edited by Tom Coenye and myself and serves as an excellent update to the highly successful first book: "Burkholderia: molecular microbiology and genomics" (http://www.horizonpress.com/backlist/horizonbioscience/burk.html).

Research division

Organisms and Environment

I was born in Penang, Malaysia, but grew up as a "Brummy" in Walsall, West Midlands, UK. My undergraduate studies (B.Sc. in Applied Biology; 1987) were completed at the then University of Wales Institute of Science and Technology, which subsequently became part of Cardiff University. I completed a Ph.D. (Molecular Microbiology; 1991) at the Medical Research Council's National Institute for Medical Research at Mill Hill, London, working on mycobacteria, the bacteria most known for causing tuberculosis.

After my PhD, I took up a postdoctoral position (1991) at the Faculty of Medicine, University of British Columbia, Vancouver, Canada. This is where I began to developing expertise in the cystic fibrosis microbiology, working on Pseudomonas aeruginosa and Burkholderia cepacia complex bacteria that cause devastating lung infections in these individuals. The two year postdoctoral position turned into a nine year stay, that included obtaining a Fellowship from the Canadian Cystic Fibrosis Foundation, moving through several positions, with a final appointment as an Associate Professor in 1997.

In June 1999, I joined Cardiff School of Biosciences, Cardiff University, as a Lecturer, returning to Wales and the institution I had first studied within. I served on the editorial board of the Journal of Clinical Microbiology from 2000 to 2008, and continue to guest review for the American Society for Microbiology journals as well as many other science journals and grant funding bodies. In August, 2011, after previous promotions to Senior Lecturer (2004), and Reader (2007), I was promoted to Professor. I currently serve as the Postgraduate Tutor for the Organisms and Environment Division and coordinate the final year module "Human Infectious Diseases."

While Burkholderia bacteria and cystic fibrosis microbiology remain major research foci, my interests are still wide and I am always getting involved in lots of very interesting molecular microbiology projects. In the last few years, we made a very exciting discovery that the Burkholderia bacteria I had studied as pathogens, also make some very potent antibiotics which kill other multidrug resistant bacteria and fungi. Antibiotic discovery has now become a major new research focus for me.

The aim of my group's research is to dissect the natural biology and virulence of opportunistic bacterial pathogens, using molecular and genomic research strategies. In particular, we have focussed on Pseudomonas aeruginosa and Burkholderia cepacia complex bacteria which cause problematic lung infections in people with cystic fibrosis (CF), with notable discoveries from these studies including the following.

Advances in cystic fibrosis microbiology

Adaption of P. aeruginosa to a non-motile phenotype during chronic infection in CF

In 1994, we described that approximately 40% of P. aeruginosa CF isolates loose their ability to express the bacterial flagellum during their adaption to chronic lung infection (see Mahenthiralingam et al. 1994).

PCR-fingerprinting methods and the molecular epidemiology of CF pathogens

We were the first to develop Random Amplified Polymorphic DNA (RAPD) typing schemes for P. aeruginosa and B. cepacia complex bacteria (See Mahenthiralingam et al. 1996). These pioneering studies were expanded to several national and international surveys of CF pathogen epidemiology and facilitated the development of robust infection control guidelines.

A DNA marker for transmissible B. cepacia complex bacteria

From RAPD analysis, we identified a fragment of DNA designated the "B. cepacia Epidemic Strain Marker" (BCESM; see Mahenthiralingam et al. 1997) from which PCR diagnostics were developed and applied by international researchers to track problematic strains and aid CF infection control.

Rapid DNA diagnostics for B. cepacia complex species identification

In 1997 "B. cepacia" isolates were shown to belong to multiple, difficult to identify, bacterial species. We developed the first accurate molecular species tests using the recA gene, a method that became one of the global standards for Burkholderia taxonomy (see Mahenthiralingam et al. 2000 and Payne et al. 2005).

The identification that B. cenocepacia could replace B. multivorans infection in people with CF

Prior to 1995, "B. cepacia" infected CF individuals were often cohorted at treatment clinics. Using both RAPD and recA analysis, we were able to identify strain transmission, super-infection over B. multivorans and poor clinical outcome associated with B. cenocepacia infection (see Mahenthiralingam et al. 2001); again this key understanding helped improved infection control in CF.

Identification of the first B. cenocepacia pathogenicity island

After collaborative initiation of the first B. cepacia complex genome sequence in 2000 (published in 2009; see Holden et al. 2009), we used the sequence data to show the "B. cepacia epidemic strain marker" was in fact part of a novel B. cenocepacia pathogenicity island encoding virulence and important quorum sensing regulatory genes (see Baldwin et al. 2004).

Collaborative development of a multilocus sequence typing (MLST) scheme for the B. cepacia complex

As an expansion of recA analysis, we played an integral part in the collaborative development of a B. cepacia complex MLST scheme (see Baldwin et al. 2005; see http://pubmlst.org/bcc). Several ground-breaking findings stemmed from MLST analysis including: (i) the linkage of a microbial metagenome to a cultivable, globally distributed Bcc strain (see Mahenthiralingam et al. 2006); (ii) the unequivocal demonstration of clonality between environmental and clinical Burkholderia strains (see Baldwin et al. 2007); (iii) multiple detailed studies of B. cepacia population biology; (iv) characterisation of multiple new B. cepacia complex species, including B. lata and B. contaminans (see Vanlaere et al. 2009) and, (v) the expansion of the MLST scheme to include all Burkholderia species (see Spilker et al. 2009).

Advances in Burkholderia genomics

Genomic analysis of Burkholderia bacteria

We have collaboratively initiated and characterised multiple Burkholderia genomes, including assisting in the annotation of putative virulence factors in the B. xenovorans genome (see Chain et al. 2006), the first signature tagged transposon mutagenesis study of B. vietnamiensis in ecological settings (see O'Sullivan et al. 2007) and first publication of a B. cepacia complex genome, that of B. cenocepacia J2315 (see Holden et al. 2009).

Global gene expression analysis of Bcc bacteria

We were involved in the collaborative development of a B. cenocepacia J2315 microarray and hence were able for the first time to examine the global gene expression of this pathogen during growth in CF sputum (see Drevinek et al. 2008). Subsequently, my group to ran an international B. cenocepacia microarray program with funding from the US Cystic Fibrosis Foundation Therapeutics that has led to multiple novel insights into the gene expression behind virulence, antibiotic resistance, quorum sensing and biofilm lifestyles of these bacteria.

Stable evolution of antibiotic resistance in B. cenocepacia

We recently showed that when the genome reference isolate, B. cenocepacia J2315, is exposed to single antibiotic, stable resistance to that antibiotic and multiple others will occur (Sass et al. 2011). This finding was corroborated by the analysis of clones that had naturally circulated within the CF population and caused an outbreak of infection in 2008. These recent clinical isolates had evolved the same antibiotic resistance profile over the 19 years that had past since the isolate of J2315 in 1989. Microarray analysis demonstrated that the gene expression changes behind the evolved resistance were stable and not lost in the absence of the antibiotic.

Advances in industrial and applied microbiology

Several projects with industrial partners have been carried out applying our expertise in molecular microbiology to questions in applied microbiology:

Bacterial contamination of fuels

As part of an NERC-CASE PhD studentship, Judith White worked with ECHA Microbiology Ltd. (http://www.echamicrobiology.co.uk), using DNA sequence-based identification approaches and cultivation-independent molecular methods to systematically survey the diversity of bacterial fuel contaminants (see White et al. 2011). A notable finding from this study was the over-representation of Pseudomonas species bacteria in the cultivation-based analysis which was not evident from the cultivation-independent bacterial diversity analysis.

Bacterial contamination in industry

We have also been working with Unilever Research and Development, Port Sunlight, (http://www.unilever.co.uk) who were the CASE partners for a BBSRC studentship that sponsored Laura Rushton (ne Thomas). Laura examined microbial contamination in industrial processes and bacterial preservative resistance and is now continuing this research as a part of Technology Strategy Board sponsored Knowledge Transfer Partnership. Rebecca Weiser has also started a BBSRC PhD studentship that is CASE funded by Unilever Research and Development, to examine Pseudomonas aeruginosa preservative resistance.

Genetic fingerprint and tracking of bacterial probiotics

With funding from Cultech Ltd., we employed our knowledge of Random Amplified Polymorphic DNA typing methods to develop a strategy for tracking Lactic Acid Bacteria during the consumption of probiotics (see Mahenthiralingam et al. 2009). Matthew Bull is continuing this work as part of a BBSRC-CASE PhD studentship with Cultech Ltd.

Burkholderia: A source for antibiotic discovery

Recently we were able to show that novel polyketide antibiotics are produced by B. cepacia complex bacteria which kill other Burkholderia bacteria and multidrug resistant bacteria. The biosynthetic pathway and chemistry of one of these antibiotics, enacyloxin IIa, was characterised in detail (see Mahenthiralingam et al. 2011) and we hope this exciting discovery lead to further research on Burkholderia as a source of novel antibiotics.

Collaborators

International

International Burkholderia cepacia Working Group (IBCWG; http://www.go.to/cepacia). I collaborate widely with many participants in this international working group and have also organized the 1999 (Banff, Canada) and 2003 annual meetings (London, UK)
Prof. David Speert and Dr. James Zlosnik, University of British Columbia, Vancouver, Canada
Prof. Peter Vandamme and Prof. Tom Coenye, University of Gent, Gent, Belgium
Prof. John LiPuma, University of Michigan, Ann Arbor, Michigan USA
Prof. Leo Eberl, University of Zurich, Zurich, Switzerland
Prof. Miguel Valvano, Centre for Infection and Immunity, Queen's University of Belfast, Belfast
Dr. Pavel Drevinek, 2^nd Medical School, University of Prague, Prague, Czech Republic

National

Prof. Andrew Weightman, Prof. Lynne Boddy, Dr. Colin Berry, Dr. Hilary Rogers and Dr. Julian Marchesi at Cardiff School of Biosciences, Cardiff University
Dr. Adam Baldwin and Prof. Chris Dowson, University of Warwick, Coventry
Prof Gregory Challis and Dr Lijiang Song, Department of Chemistry, University of Warwick, Coventry
Prof Julian Parkhill, The Sanger Institute, Hinxton, Cambridge
Dr. Andrew Jones, Dr. William Flight and Dr. Rowland Bright-Thomas, Manchester Adult Cystic Fibrosis Centre, University Hospital of South Manchester NHS Foundation Trust, Manchester
Dr. Sue Plummer, Cultech Ltd, Swansea, UK
The UK CF Microbiology Consortium (http://www.cfmicrobiology.org.uk)
NISCHR Microbiology and Infection Translational Research Group (MITREG) and Cystic Fibrosis Research Group (http://www.mitreg.co.uk/page.cfm?orgid=951&pid=62808)

Grants

UK Cystic Fibrosis Trust
US Cystic Fibrosis Foundation
The Leverhulme Trust
Technology Strategy Board & Knowledge Transfer Partnerships
Natural Environment Research Council
Biolology and Biotechnology Research Council
Society for General Microbiology
Society for Applied Microbiology
Cultech Ltd.
Echa Microbiology Ltd.
Unilever Research and Development, UK

Current group members

Dr. Laura Rushton (ne Thomas) (ThomasL32@cardiff.ac.uk)
Mr. Matthew Bull (BullMJ2@cardiff.ac.uk)
Ms. Rebecca Weiser (WeiserRM@cardiff.ac.uk)

Past group members

Dr. Andrea Sass
Dr. Othman Boaisha
Dr. Judith White
Dr. Helen Rose
Dr. Pavel Drevinek
Dr. Louise O'Sullivan
Dr. Adam Baldwin
Dr. Deborah Lewis
Dr. George Payne
Dr. Saber Yezli
Ms. Angela Marchbank

Yr Athro Eshwar Mahenthiralingam

Trosolwg

Research overview

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