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An international group of scientists coordinated by Stewart Cole of the Institut Pasteur has just discovered the genetic basis for the synthesis of the Mycobacterium ulcerans toxin, responsible for Buruli ulcer.
A rapidly-expanding emerging disease, Buruli ulcer is the one of the most common mycobacterial infections after tuberculosis and leprosy. Caused by the bacterium Mycobacterium ulcerans, advanced disease is indicated by serious ulceration of the skin, often destroying muscles and bones. It leaves its victims seriously disfigured, even disabled.
The World Health Organization considers Buruli ulcer to be an emerging threat to public health. This disease is rife in about 30 countries - in wetland areas of the tropical and subtropical regions of Africa, Latin America, Asia and the western Pacific. It is especially widespread in West Africa, where the spread of M. ulcerans has been accelerating since the 80s. For example, in some regions of Ghana and the Ivory Coast up to 22% of the population are affected.
The teams* led by Stewart Cole, Head of the Bacterial Molecular Genetics Unit at the Institut Pasteur and coordinated by Timothy Stinear have just determined the genetic blueprint for the production of mycolactone, the Mycobacterium ulcerans polyketide toxin that destroys tissues and inhibits the immune system. They demonstrated that the mycolactone synthesis genes are harboured by a giant plasmid (a plasmid is a group of genes separate from the chromosome of the bacterium, and which can be easily transmitted from one bacterium to another through horizontal transfer). This plasmid consists of 80 genes, six of which are involved in synthesizing the toxin.
The authors note that this genetic system is likely to be very unstable as the toxin genes are unusually large and contain unprecedented levels of repeating DNA sequences. High mutation rates may account for the sudden appearance of Buruli ulcer epidemics as some strains of the bacterium may produce toxins that give it a survival advantage. Such mutations may coincide with increased virulence or transmissibility to humans.
"Decoding how the toxin is synthesized should make it possible to use new approaches to combat Mycobacterium ulcerans infections", the researchers conclude.
The scientists will now endeavour to develop these new approaches.
This major advance should accelerate the development of therapeutic strategies, sorely lacking at present, to combat the disease and is a significant source of hope in the fight against Buruli ulcer.
"Giant plasmid-encoded polyketide synthases produce the macrolide toxin of Mycobacterium ulcerans". PNAS, 2004.
Timothy P. Stinear (1), Armand Mve-Obiang (2), Pamela L.C. Small (2), Wafa Frigui (1), Melinda J. Pryor (1,3), Roland Brosch (1), Grant A. Jenkin (4), Paul D.R. Johnson (1,5), John K. Davies (4), Richard E. Lee (6), Sarojini Adusumili (2), Thierry Garnier (1), Stephen F. Haydock (7), Peter F. Leadlay (7), and Stewart Cole (1)
* 1. Bacterial Molecular Genetics Unit, Institut Pasteur
2. Department of Microbiology, University of Tennessee, Knoxville, USA
3. Platform 4-Genome Analysis and Integration, Genopole, Institut pasteur
4. Department of Microbiology, Monash University, Clayton, Australia
5. Department of Infectious Diseases, Austin Hospital, Heidelberg, Australia
6. Department of Pharmaceutical Sciences, University of Tennessee, Memphis, USA
7. Department of Biochemistry, University of Cambridge, Cambridge, United Kingdom
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