Open AccessTranscriptional regulator-induced phenotype screen reveals drug potentiators in Mycobacterium tuberculosis
Author(s) -
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
Publication year - 2020
Publication title -
nature microbiology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 7.305
H-Index - 79
ISSN - 2058-5276
DOI - 10.1038/s41564-020-00810-x
Subject(s) - mycobacterium tuberculosis , regulator , potentiator , effector , phenotype , biology , gene , gene regulatory network , genetics , transcriptional regulation , transposon mutagenesis , mutant , tuberculosis , computational biology , transposable element , gene expression , microbiology and biotechnology , medicine , pathology
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.