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

Nat Microbiol. 2021 Jan;6(1):44-50. doi: 10.1038/s41564-020-00810-x. Epub 2020 Nov 16.


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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Antitubercular Agents / pharmacology*
  • Gene Expression Regulation, Bacterial / drug effects
  • Gene Regulatory Networks / genetics*
  • Isoniazid / pharmacology*
  • Mycobacterium tuberculosis / drug effects*
  • Mycobacterium tuberculosis / genetics
  • Stress, Physiological / physiology
  • Transcription, Genetic / genetics*


  • Antitubercular Agents
  • Isoniazid