The genome sequence of Mycobacterium tuberculosis reveals cytochromes P450 as novel anti-TB drug targets

Mycobacterium tuberculosis, the causative agent of TB, has re-emerged as a global threat to health. The spread of this pathogenic bacterium is due largely to the development and proliferation of multi-drug resistant strains. The M tuberculosis genome sequencing project was completed in 1998 and revealed a large number of novel proteins as possible drug targets. One of the most unusual features of the M tuberculosis proteome is the large number of cytochrome P450 enzymes. There are 20 putative P450s encoded by IM tuberculosis, far more than in other sequenced bacterial genomes. We have cloned and expressed a number of these P450s in Escherichia coli, and have purified two P450s for structural and drug-interaction studies. Of these P450s, the most attractive target is the product of the Rv0764c gene (P450 MT1) - a homologue of the eukaryotic 14 alpha-lanosterol demethylases. Yeast and fungal demethylases are effectively inactivated by a range of azole-containing compounds ('azole antifungals'), leading to loss of cellular viability. P450 MT1 also binds tightly to these anti-fungals (including ketoconazole, miconazole and fluconazole), providing hope that this class of compounds may also be effective anti-tuberculosis drugs. (C) 2000 Society of Chemical Industry.