Transcriptional regulator-induced phenotype screen reveals drug potentiators in Mycobacterium tuberculosis

Transposon-based strategies provide a powerful and unbiased way to study the bacterial stress response(1-8), but these approaches cannot fully capture the complexities of network-based behaviour. Here, we present a network-based genetic screening approach: the transcriptional regulator-induced phenotype (TRIP) screen, which we used to identify previously uncharacterized network adaptations of Mycobacterium tuberculosis to the first-line anti-tuberculosis drug isoniazid (INH). We found regulators that alter INH susceptibility when induced, several of which could not be identified by standard gene disruption approaches. We then focused on a specific regulator, mce3R, which potentiated INH activity when induced. We compared mce3R-regulated genes with baseline INH transcriptional responses and implicated the gene ctpD (Rv1469) as a putative INH effector. Evaluating a ctpD disruption mutant demonstrated a previously unknown role for this gene in INH susceptibility. Integrating TRIP screening with network information can uncover sophisticated molecular response programs. In this study, the authors use a transcriptional regulator-induced phenotype screen coupled with network analysis to characterize adaptations of Mycobacterium tuberculosis to the first-line anti-tuberculosis drug isoniazid. They identify the transcriptional factor mce3R and the CtpD effector to have a role in Mycobacterium susceptibility to isoniazid.

Automated summary

The study utilizes a transcriptional regulator-induced phenotype screen coupled with network analysis to characterize adaptations of Mycobacterium tuberculosis to the first-line anti-tuberculosis drug isoniazid, identifying the transcriptional factor mce3R and the CtpD effector to have a role in Mycobacterium susceptibility to isoniazid.