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

2020; Nature Portfolio; Volume: 6; Issue: 1 Linguagem: Inglês

10.1038/s41564-020-00810-x

2058-5276

Shuyi Ma, Robert Morrison, Samuel J. Hobbs, Vijay Soni, Jessica Farrow-Johnson, Andrew Frando, Neil Fleck, Christoph Grundner, Kyu Y. Rhee, Tige R. Rustad, David R. Sherman,

Bacterial Genetics and Biotechnology

Transposon-based strategies provide a powerful and unbiased way to study the bacterial stress response1-8, 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.