The genome sequence ofMycobacterium 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 M 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 14α-lanosterol demethylases. Yeast and fungal demethylases are effectively inactivated by a range of azole-containing compounds (‘azole anti-fungals’), 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.