WIREDGOV

A key mechanism by which a bacterial pathogen causes the deadly tropical disease
melioidosis has been discovered by an international team of scientists.

The findings are published recently in the journal Science and show how a toxin produced by
the bacterium Burkholderia pseudomallei kills cells by preventing protein synthesis. The
study, led by the University of Sheffield, paves the way for the development of novel
therapies to combat the bacterium which infects millions of people across South East Asia and Northern Australia.

Using intense X-rays at Diamond Light Source, the UK’s national synchrotron facility, and at the European Synchrotron Radiation Facility (ESRF) in Grenoble, France, the research team solved the structure of a protein from Burkholderia, the function of which was initially unknown.

“The information gathered from the structure suggested that the protein was a previously
unsuspected toxin and sparked a search for its mode of action. This eventually led to the
discovery of how it prevents human cells from making proteins and helped us to understand how it causes cell death,” says research lead Professor David Rice from the Department of Molecular Biology and Biotechnology at the University of Sheffield.

Melioidosis, along with HIV and tuberculosis, is one of the top three causes of death by
infectious disease in parts of South East Asia and arises from infection by the bacterium
which thrives in water and warm, moist soils and can enter the body through the lungs or
through open wounds.

It causes either an acute form of the disease which presents immediately upon infection, or it can lay dormant in the body emerging many years, and often decades, later. In the acute form of the disease, even with a long course of treatment, mortality rates in endemic areas can be as high as 40 per cent. With a wide range of symptoms, melioidosis can be difficult to diagnose, hampering medical intervention.

“This disease is an everyday reality for many people living in the endemic areas and our
findings will allow us to test if an inactivated toxin might be effective as a component of a
vaccine,” says Professor Rick Titball, a member of the team from the University of Exeter.
The delayed action of the bacteria has led to it being dubbed the ‘Vietnam time bomb’
following the recognition that many US military personnel who served in Vietnam have been infected. “Now that we know of the existence of this toxin it opens up opportunities for the development of novel drugs that could block its effects,” says University of Sheffield
Professor, Stuart Wilson.

The study involved a consortium of UK scientists from the University of Sheffield, the
University of Exeter, Diamond Light Source and the Defence Science and Technology
Laboratory at Porton Down. European and international partners included: the European
Synchrotron Radiation Facility (ESRF) in Grenoble, France; Universiti Kebangsaan
Malaysia; the Malaysia Genome Institute; DSO National Laboratories, Singapore, and the
Genome Institute of Singapore.

Kevin van Cauter, HE Advisor with the British Council commented “We are thrilled that PMI2 funding supported this international collaboration and are excited by the potential impact of the work.”

These groups now plan to seek funding to continue the work and investigate potential
applications of the toxin to fight other diseases, such as cancer, where it might usefully be
employed in targeted therapies to prevent the proliferation of cancer cells.

For further information and to arrange interviews:

Shemina Davis, University of Sheffield press office, tel 0114 222 5339, email:
shemina.davis@sheffield.ac.uk

Clare Elsley, Campus PR, tel 0113 357 2102, email 07767 685168, email
clare@campuspr.co.uk

Vicky Torraca, Defence Science and Technology Laboratory, tel 01980 658666, 07901
892660, press@dstl.gov.uk

NOTES TO EDITORS

1. The study, entitled A Burkholderia pseudomallei Toxin Inhibits Helicase Activity of
Translation Factor eIF4A is published in the latest issue of Science. Copies of the
embargoed Science paper may be distributed only by the AAAS Office of Public
Programs, to working journalists. Please contact +1-202-326-6440 or
scipak@aaas.org

2. The study was funded by a number of agencies:

·          Biotechnology & Biological Sciences Research Council ()
·          British Council PMI2 Research Cooperation Programme ()
·          CONACYT
·          Engineering & Physical Sciences Research Council ()
·          Ministry of Defence ( )
·          Ministry of Science, Technology and Innovation, Government of
·          Wellcome Trust