Title | Transcriptional regulator-induced phenotype screen reveals drug potentiators in Mycobacterium tuberculosis. |
Publication Type | Journal Article |
Year of Publication | 2021 |
Authors | Ma S, Morrison R, Hobbs SJ, Soni V, Farrow-Johnson J, Frando A, Fleck N, Grundner C, Rhee KY, Rustad TR, Sherman DR |
Journal | Nat Microbiol |
Volume | 6 |
Issue | 1 |
Pagination | 44-50 |
Date Published | 2021 01 |
ISSN | 2058-5276 |
Keywords | Antitubercular Agents, Gene Expression Regulation, Bacterial, Gene Regulatory Networks, Isoniazid, Mycobacterium tuberculosis, Stress, Physiological, Transcription, Genetic |
Abstract | 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. |
DOI | 10.1038/s41564-020-00810-x |
Alternate Journal | Nat Microbiol |
PubMed ID | 33199862 |
PubMed Central ID | PMC8331221 |
Grant List | T32 AI007509 / AI / NIAID NIH HHS / United States U19 AI106761 / AI / NIAID NIH HHS / United States U19 AI111276 / AI / NIAID NIH HHS / United States U19 AI135976 / AI / NIAID NIH HHS / United States |