A Mycobacterium tuberculosis sigma factor network responds to cell-envelope damage by the promising anti-mycobacterial thioridazine

Noton K. Dutta, Smriti Mehra, Deepak Kaushal

Research output: Contribution to journalArticlepeer-review

Abstract

Background: Novel therapeutics are urgently needed to control tuberculosis (TB). Thioridazine (THZ) is a candidate for the therapy of multidrug and extensively drug-resistant TB. Methodology/Principal Findings: We studied the impact of THZ on Mycobacterium tuberculosis (Mtb) by analyzing gene expression profiles after treatment at the minimal inhibitory (1× MIC) or highly inhibitory (4× MIC) concentrations between 1-6 hours. THZ modulated the expression of genes encoding membrane proteins, efflux pumps, oxido-reductases and enzymes involved in fatty acid metabolism and aerobic respiration. The Rv3160c-Rv3161c operon, a multi-drug transporter and the Rv3614c/3615c/3616c regulon, were highly induced in response to THZ. A significantly high number of Mtb genes co-expressed with σB (the σ B regulon) was turned on by THZ treatment. σB has recently been shown to protect Mtb from envelope-damage. We hypothesized that THZ damages the Mtb cell-envelope, turning on the expression of the σB regulon. Consistent with this hypothesis, we present electron-microscopy data which shows that THZ modulates cell-envelope integrity. Moreover, the Mtb mutants in σH and σE, two alternate stress response sigma factors that induce the expression of σB, exhibited higher sensitivity to THZ, indicating that the presence and expression of σB allows Mtb to resist the impact of THZ. Conditional induction of σB levels increased the survival of Mtb in the presence of THZ. Conclusions/Significance: THZ targets different pathways and can thus be used as a multi-target inhibitor itself as well as provide strategies for multi-target drug development for combination chemotherapy. Our results show that the Mtb sigma factor network comprising of σH, σE and σB plays a crucial role in protecting the pathogen against cell-envelope damage.

Original languageEnglish (US)
Article numbere10069
JournalPloS one
Volume5
Issue number4
DOIs
StatePublished - 2010

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Agricultural and Biological Sciences(all)
  • General

Fingerprint Dive into the research topics of 'A Mycobacterium tuberculosis sigma factor network responds to cell-envelope damage by the promising anti-mycobacterial thioridazine'. Together they form a unique fingerprint.

Cite this