Identification of new drug targets and assembly of the TB cell wall (#60)
Tuberculosis (TB) continues to cause more deaths and human suffering than any other infectious disease. In addition to peptidoglycan (PG), arabinogalactan (AG) and lipoarabinomannan (LAM) are two other carbohydrate-based macromolecules which are essential components of the Mycobacterium tuberculosis cell wall. Fully matured AG is esterified at its non-reducing terminus with long chain mycolic acids, thus acting as a core molecular scaffold connecting PG to the outer mycolate layer. This huge cell wall complex ultimately provides the TB-bacilli with structural support, rigidity and a primary defensive barrier against toxic insult. By adopting a range of biochemical and molecular genetic approaches, we have made significant advances in delineating the genetic and molecular basis of AG and LAM biosynthesis. Mycobacterial cell wall assembly is currently back in vogue. This is, perhaps, partly due to recent findings that describes benzothiazinones (BTZ) as a new class of molecules targeting the early stages of AG biosynthesis. This, in addition to the discovery that a potent combination of meropenem and clavulanate exhibits inhibitory activity against a range of M. tuberculosis and Multi-Drug Resistant tuberculosis (MDR-TB) strains, provides corroborating evidence supporting the notion that targeting critical steps of Mycobacterial cell wall assembly is a valid and worthwhile approach to the discovery of novel drug targets. This talk aims to cover various aspects of Mycobacterial PG, AG and LAM biosynthesis, specifically focusing on our laboratories multi-disciplinary experimental approaches, contextualized with a summary our recent findings relating to the overall assembly of the Mycobacterial cell wall and how we are looking to develop an anti-TB drug discovery program at Birmingham.