Vitamin B6 biosynthesis is essential for survival and virulence of Mycobacterium tuberculosis

P>With 500 000 cases of multidrug-resistant tuberculosis there is an urgent need for attractive targets to enable the discovery of novel antimycobacterials. The biosynthesis of essential cofactors is of particular interest as these pathways are absent in man and their inhibition is expected to affect the metabolism of Mycobacterium tuberculosis at multiple sites. Our data demonstrate that the pathogen synthesizes pyridoxal 5-phosphate (PLP), the bioactive form of vitamin B6, by a heteromeric PLP synthase composed of Pdx1 (Rv2606c) and Pdx2 (Rv2604c). Disruption of the pdx1 gene generated a strictly B6 auxotrophic M. tuberculosis mutant, Delta pdx1. Removal of the cofactor during exponential growth or stationary phase demonstrated the essentiality of vitamin B6 biosynthesis for growth and survival of the pathogen in culture. In a tuberculosis dormancy model based on gradual oxygen depletion, de novo biosynthesis of PLP was required for regrowth of the bacillus after direct oxygen exposure. The Delta pdx1 mutant showed a severe growth defect in immunocompetent mice: bacilli applied intranasally failed to persist in host tissues and were quickly cleared. We conclude that vitamin B6 biosynthesis is required for survival of M. tuberculosis in vivo and thus might represent a candidate pathway for the development of new antitubercular agents.