A chemical genetics approach to identify targets essential for the viability of mycobacteria

Abstract

The key goals for the development of new tuberculosis drugs are to shorten the treatment time and to have efficacy against latent and multi-drug resistant tuberculosis. Moreover, the best drug targets should be essential in both active and dormant phases of Mycobacterium tuberculosis infection. To achieve this, we chose to use a forward chemical genetics approach, which involves screening a library of compounds on M. bovis BCG selecting only compounds that result in death or growth inhibition. We isolated M. bovis BCG mutants resistant to two structurally-related compounds. The magnesium and cobalt transport transmembrane protein, CorA, was identified as a putative target based on the mapping of mutations to the corA gene in the mutant strains. However, due to the non-essentiality of the corA gene and the bactericidal effect of the compounds, we suggest that CorA is not the actual target and that it mediates an indirect mechanism of resistance.