MAGPIE Project: The Structure, Biosynthesis and Assembly of the Mycobacterial Cell Envelope

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. In this coordinated set of projects, the investigators are combining their particular expertise in analysing the Mtb cell wall to improve our understanding of these remarkable structures and the metabolic processes that are required for their assembly.

Communication to the general public will be channelled through the University Press Office at Birmingham (http://www.newscentre.bham.ac.uk/office.htm) and Leciester (http://www.le.ac.uk/press/), which have 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 Mycolyl-Arabinogalactan-Peptidoglycan Initiative and Exploitation (MAGPIE) project is aimed at coordinating a continued integrated investigation and exploitation of the basic physiology of the mycolyl-arabinogalactan-peptidoglycan complex and associated free lipids in the cell envelope of Mycobacterium tuberculosis. Mycolic acids are essential envelope components and key drug targets; substantial current progress will be vigorously continued into understanding the enzymology of mycolate synthesis, particularly for condensing and tranferase enzymes. New drugs, targeting mycolate-condensing enzymes, will be synthesized, tested and new analogues developed. Mycolates are supported on an arabinogalactan, linked to the basal wall peptidoglycan; the glycosyltransferases involved in the assembly of this complex 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. The expression of cell envelope components in the M. tuberculosis complex, in vivo and in vitro, will be studied, using sensitive methods which will also continue to be applied to the detection of ancient and modern disease. The role of human CD1 recognition systems will be exhaustively explored, revealing innovative directions for the treatment or prevention of tuberculosis. All of the above prime investigations will exploit the full power of modern genomics, as will new areas being developed, such as the role of P450 enzymes, N-acetyl transferases, siderophores and phosphatidylinositol-based lipoglycans from related mycolata taxa.