Scientists make TB bug suicidal
21 March 2010
Scientists at a BBSRC Institute have identified a new class of drug target that tricks tuberculosis bacteria into suicidal self-poisoning. New therapies are urgently required to control the tuberculosis pandemic. Even in the UK cases are on the rise.
"With the advent of antibiotics, TB became treatable and at one point eradication was believed possible," says Dr Steph Bornemann from the John Innes Centre.
"But TB has re-emerged as a major global health threat due to poverty, a deadly synergy with HIV and the emergence of drug resistant strains that are virtually untreatable with current therapies."
Mycobacterium tuberculosis is the cause of tuberculosis and the leading cause of death worldwide from bacterial pathogens. It claims about 2 million lives every year.
Scientists at the John Innes Centre in Norwich and the Albert Einstein College of Medicine of Yeshiva University (Einstein) in New York identified the role that an enzyme called GlgE plays in Mycobacterium tuberculosis. The two research groups made the discovery independently using different approaches. Together the scientists have identified a four-step metabolic pathway involving GlgE that represents a new target for anti-tuberculosis drugs.
The target works in a completely different way from current drugs. Blocking GlgE causes the toxic build-up of a modified sugar called maltose 1-phosphate within the bacterial cells. The bacteria respond by producing even more of the sugar in a misguided and lethal stress response.
Given time, the emergence of resistance to antibiotics is almost inevitable. In readiness of such an eventuality, the scientists have already identified a secondary drug target that would mitigate the most likely mode of resistance to anti-GlgE drugs.
GlgE does not exist in humans so it is safe to inactivate it with a drug. Another sugar called trehalose commonly found in the human diet could conceivably be used to make an anti-GlgE drug more potent. If dietary trehalose reached the bacteria it would increase the levels of maltose 1-phosphate even further.
"This pathway has never previously been targeted by antimicrobials and offers a treatment option very different from antibiotics in use," says Dr William Jacobs, Jr. from Einstein, senior and corresponding author of the study.
The John Innes Centre is an Institute of BBSRC. Dr Steph Bornemann's work on this project was also funded by BSBRC.
A patent was filed in November 2009 on behalf of Einstein and JIC. John Innes Centre's rights in the technology have been assigned to JIC's IP management and technology transfer company, PBL, Norwich. PBL and Einstein are working together to secure the intellectual property and engage with partners to develop this innovation and find inhibitors of GlgE that could be developed into anti-TB drugs.
Notes to editors
'Self-poisoning of Mycobacterium tuberculosis by inhibition of GlgE reveals a new class of drug target' doi: 10.1038/nchembio.340 will be published online by Nature Chemical Biology on 21 March 2010 ahead of World TB Day on 24 March.
The John Innes Centre, www.jic.ac.uk, is an independent, world-leading research centre in plant and microbial sciences with over 500 staff. JIC is based on Norwich Research Park and carries out high quality fundamental, strategic and applied research to understand how plants and microbes work at the molecular, cellular and genetic levels. The JIC also trains scientists and students, collaborates with many other research laboratories and communicates its science to end-users and the general public. The JIC is grant-aided by the Biotechnology and Biological Sciences Research Council.
About Albert Einstein College of Medicine of Yeshiva University
Albert Einstein College of Medicine of Yeshiva University is one of the nation's premier centers for research, medical education and clinical investigation. During the 2009-2010 academic year, Einstein is home to 2,775 faculty members, 722 M.D. students, 243 Ph.D. students, 128 students in the combined M.D./Ph.D. program, and approximately 350 postdoctoral research fellows. In 2009, Einstein received more than $155M in support from the NIH. This includes the funding of major research centers at Einstein in diabetes, cancer, liver disease, and AIDS. Other areas where the College of Medicine is concentrating its efforts include developmental brain research, neuroscience, cardiac disease, and initiatives to reduce and eliminate ethnic and racial health disparities. Through its extensive affiliation network involving five medical centers in the Bronx, Manhattan and Long Island - which includes Montefiore Medical Center, The University Hospital and Academic Medical Center for Einstein - the College of Medicine runs one of the largest post-graduate medical training programs in the United States, offering approximately 150 residency programs to more than 2,500 physicians in training.
For more information, please visit www.einstein.yu.edu
Plant Bioscience Limited (PBL) www.pbltechnology.com is a technology development and intellectual property management company owned in equal parts by the John Innes Centre www.jic.ac.uk, The Sainsbury Laboratory www.tsl.ac.uk, and the Biotechnology and Biological Sciences Research Council. PBL promotes the development and commercial uptake of academic research results for public use and benefit and is specialised in life sciences.
BBSRC is the UK funding agency for research in the life sciences. Sponsored by Government, BBSRC annually invests around £450M in a wide range of research that makes a significant contribution to the quality of life in the UK and beyond and supports a number of important industrial stakeholders, including the agriculture, food, chemical, healthcare and pharmaceutical sectors.
BBSRC provides institute strategic research grants to the following:
- The Babraham Institute
- Institute for Animal Health
- Institute for Biological, Environmental and Rural Studies (Aberystwyth University)
- Institute of Food Research
- John Innes Centre
- The Genome Analysis Centre
- The Roslin Institute (University of Edinburgh)
- Rothamsted Research
The Institutes conduct long-term, mission-oriented research using specialist facilities. They have strong interactions with industry, Government departments and other end-users of their research.
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