Investigation of late-stage mycobacterial cell wall biosynthesis

Tuberculosis (TB) is a bacterial infectious disease caused by the organism Mycobacterium tuberculosis. Affecting large parts of the world's population, in particular in the context of poverty, TB remains a top priority among WHO-led disease containment efforts. M. tuberculosis is an extremely successful pathogen, in part because its unique cell wall provides an almost impenetrable barrier to host defences and contributes to resistance against many common antibiotics, such as penicillin. TB is treated with a cocktail of four frontline drugs, however increasing multi-drug resistance compromises the efficacy of this regimen. It is generally agreed that reversing the global TB epidemic requires new inhibitors hitting novel targets.

Survival of M. tuberculosis rests critically on the integrity of its unique cell wall, and enzymes contributing to cell wall biosynthesis often emerge as the targets of new drug-like inhibitors. In this regard, a better understanding of cell wall assembly will support the quest for new therapies, which are urgently required. The mycobacterial cell wall is built through a series of complex biosynthetic "steps" and understanding how the genes and enzymes involved in this pathway work is fundamental for us to develop new drugs to treat this disease. It is hoped that by investigating the complex cell wall biochemistry of M. tuberculosis, we will be able to find a "chink in the armour" and develop new therapies by exploiting novel drug targets.

Our proposal will shed new light on the genetic and biochemical processes that govern the way in which mycobacteria assembles its cell wall. We will follow two lines of investigation. Firstly, we plan to undertake a detailed investigation of the genetic processes that govern the latter stages of cell wall formation and how these gene products interact with each other in order to direct the final maturation of the cell envelope. Secondly, we will elucidate the molecular structures and biochemical mechanisms of the key proteins that are central to transporting large intermediate cell wall components across the inner membrane of the cell and how they assemble them on the mycobacterial cell surface. Improving our knowledge in this area is crucial because biochemical processes that occur on the "surface" of bacterial cells lend themselves more susceptible to inhibition by small molecules than reactions within the cell. Hence, enzymes and proteins that work at the surface of an organism may prove the more accessible targets to chemotherapy.

At the end of this project, we will have provided important information about a bacterial pathogen which is a scourge to humanity and shed new light on the mechanisms of cell wall biosynthesis in mycobacteria. This work will have a direct impact on the discovery and development of anti-tubercular inhibitors.