Towards the discovery of inhibitors against FtsZ, an essential cell division protein from Mycobacterium tuberculosis, a potential antimycobacterial target

Tuberculosis (TB) is a bacterial infection responsible for more than 1.5 million deaths per year. The emergence of multidrug-resistant TB (MDR-TB) and extensively drug-resistant TB (XDR-TB) poses an urgent need for novel antituberculosis drugs. Filamentous temperature-sensitive protein Z (FtsZ) is a bacterial homologue of mammalian tubulin. During bacterial cell division, FtsZ first polymerises into protofilaments in a GTP-dependent manner to form a highly dynamic cytokinetic structure, namely the Z-ring, at a cell midpoint. The Z-ring contracts resulting in septum formation and cell division. Thus, the FtsZ function is essential; indeed, its inhibition leads to the disruption of cell division and eventually bacterial cell death. The development of Mycobacterium tuberculosis FtsZ inhibitors has been hampered by a lack of structural data that could be exploited for structure-based drug design with a strong possibility of identifying false positive inhibitors using traditional drug discovery approaches. Through attempts to advance structural biology and the development of M. tuberculosis FtsZ inhibitors, first, we determined various crystal structures of M. tuberculosis FtsZ in complex with coumarin analogues ... (continues)