Find in Library

<i>Mycobacterium tuberculosis</i> (<i>Mtb</i>), the etiological agent of tuberculosis, is one of the most devastating infectious agents in the world. Chemical-genetic characterization through in vitro evolution combined with whole genome sequencing analysis was used identify novel drug targets and drug resistance genes in <i>Mtb</i> associated with its intracellular growth in human macrophages. We performed a genome analysis of 53 <i>Mtb</i> mutants resistant to 15 different hit compounds. We found nonsynonymous mutations/indels in 30 genes that may be associated with drug resistance acquisitions. Beyond confirming previously identified drug resistance mechanisms such as <i>rpoB</i> and lead targets reported in novel anti-tuberculosis drug screenings such as <i>mmpL3</i>, <i>ethA</i>, and <i>mbtA</i>, we have discovered several unrecognized candidate drug targets including <i>prrB</i>. The exploration of the <i>Mtb</i> chemical mutant genomes could help novel drug discovery and the structural biology of compounds and associated mechanisms of action relevant to tuberculosis treatment.