The Mycobacterial Cell Wall: Structure, Function and Biosynthesis

Tuberculosis (TB) is a life?threatening condition that can last for several years during which patients are debilitated and may disseminate the bacterium that causes the disease, Mycobacterium tuberculosis (Mtb). At least 30 million individuals worldwide will have died from TB in the last decade of the 20th century. In the UK the steady decline in TB cases over the whole of the last century halted in the mid 1980s and there has been alarming signs of increased numbers of cases in certain communities. The situation is compounded by the AIDS epidemic and by the emergence of Mtb strains that are resistant to virtually all the drugs that would normally be used to treat TB. It can be argued that, globally, Mtb is the single most important infectious agent affecting mankind. All bacteria have cells that, like plants, are enclosed in a cell wall. This protects the organism from its immediate environment and, fortuitously, presents an important target for drugs, like penicillin, that can be used to treat bacterial infections. However, Mtb has a distinctive cell wall that differs in composition from that of other bacteria; in particular it contains an exceptional amount of unique lipids (fats) and sugars. Although there are drugs that affect the unique Mtb cell wall, the current treatment for tuberculosis lasts 6 months and is potentially toxic to patients who often cease treatment early. Moreover, the efficacy of treatment is threatened by the emergence of drug-resistant strains of Mtb. There is therefore a great need for new and better drugs to treat TB.

Communication to the general public will be channelled through the University Press Office at Birmingham (http://www.newscentre.bham.ac.uk/office.htm) which has established contacts in the local and national media. The MRC Co-operative Group members will also highlight there research through personal University based Web pages, which has open access. This highlights the clinical and research elements of the MRC Co-operative Group.

The research grant is aimed at coordinating a continued integrated investigation into the basic biochemistry and physiology of the mycolyl-arabinogalactan-peptidoglycan (mAGP) complex and associated free lipids in the cell envelope of Mycobacterium tuberculosis. Mycolic acids are essential envelope components and substantial current progress will be vigorously continued into understanding the enzymology of mycolate synthesis, particularly for condensing and transferase enzymes. Mycolates are supported on an arabinogalactan, linked to the basal cell wall peptidoglycan; the glycosyltransferases involved in the assembly of this complex arabinogalactan matrix will continue to be characterised, as will the related enzymes leading to the prime envelope lipoarabinomannan immunogen. A range of characteristic waxes and antigenic acylated trehalose glycolipids are expressed on the cell surface and the detailed immunology and pathogenic role of these will be unravelled, revealing innovative directions for the treatment or prevention of tuberculosis. All of the above prime investigations will exploit the full power of a multi-disciplinary approach using biochemistry, chemistry, immunology and molecular biology.