The Mycobacterium tuberculosis Cell Envelope: unravelling complex cell wall assembly and the identification of potential new drug targets

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Mycobacterium tuberculosis is the cause of tuberculosis (TB) and is the leading bacterial burden of mortality and morbidity in the world. One third of the world's population is infected with TB, and in conjunction with HIV represents a serious problem that urgently needs addressing. TB is a disease of poverty and mostly affects young adults in their productive years, mostly in the developing world. The most recent report from the World Health Organisation states that in 2011, 8.8 million new cases of TB were reported and that 1.4 million people died from TB, corresponding to approximately 4000 deaths daily. In the UK, there were 7000 new cases of TB reported, mostly in large cities, and 75% of cases were in individuals not born in the UK. It can be argued that, globally, M. tuberculosis is the single most important infectious agent affecting mankind. Bacteria are enclosed in a cell wall which protects the organism from its immediate environment. Moreover, fortuitously, they also represent important targets for drugs like penicillin that can be used to treat bacterial infections. However, M. tuberculosis 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), sugars, and a mesh-like structure. Although, there are drugs that specifically affect the M. tuberculosis cell wall, the current treatment for TB 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 multi-drug and extensively-drug resistant (MDR and XDR) strains of M. tuberculosis. The proposed research will increase our knowledge as to the basic biology surrounding the M. tuberculosis 'cell envelope' and has the potential to generate data that will lead to the discovery of novel drug targets and potentially the characterisation of new 'hit-to-lead' chemical entities with a defined mode of action. Firstly, we will build on our previous studies on the synthesis of the major 'fats' of the cell envelope, termed mycolic acids and the mode of action of specific inhibitors. Secondly, we will extend our characterisation of the enzymes involved in the assembly of the 'sugars' which make up the key polysaccharides found in M. tuberculosis, which includes the macromolecules arabinogalactan, lipoarabinomannan and alpha-glucan. Thirdly, we will integrate our studies on peptidoglycan synthesis, the underlying molecular 'mesh' that covers the cell, into our framework of studies centered on the M. tuberculosis 'cell envelope'. The research in this application will increase our knowledge into the basic biology of the tubercle bacillus and has the potential to impact upon human health, with wide-reaching benefits both nationally and internationally. In particular, our proposed studies will have the potential to identify novel drug targets and aid in the development of new anti-tubercular compounds.