Identification of a small molecule with activity against drug-resistant and persistent tuberculosis

Research output: Contribution to journalArticle

Authors

  • Feng Wang
  • Dhinakaran Sambandan
  • Rajkumar Halder
  • Jianing Wang
  • Brian Weinrick
  • Insha Ahmad
  • Pengyu Yang
  • Yong Zhang
  • John Kim
  • Morad Hassani
  • Stanislav Huszar
  • Claudia Trefzer
  • Zhenkun Ma
  • Takushi Taneko
  • Khisi Mdluli
  • Scott Franzblau
  • Arnab Chatterjee
  • Kai Johnson
  • Katarina Mikusova
  • William R Jacobs Jr
  • Peter G Schultz

Colleges, School and Institutes

External organisations

  • Scripps Res Inst
  • Albert Einstein Coll Med
  • Albert Einstein Coll Med
  • Comenius Univ
  • EPFL
  • Global Alliance for Tuberculossi Drug Development
  • Univ Chicago
  • California Institute for Biomedical Research

Abstract

A cell-based phenotypic screen for inhibitors of biofilm formation in mycobacteria identified the small molecule TCA1, which has bactericidal activity against both drug-susceptible and -resistant Mycobacterium tuberculosis (Mtb) and sterilizes Mtb in vitro combined with rifampicin or isoniazid. In addition, TCA1 has bactericidal activity against nonreplicating Mtb in vitro and is efficacious in acute and chronic Mtb infection mouse models both alone and combined with rifampicin or isoniazid. Transcriptional analysis revealed that TCA1 down-regulates genes known to be involved in Mtb persistence. Genetic and affinity-based methods identified decaprenyl-phosphoryl-β-D-ribofuranose oxidoreductase DprE1 and MoeW, enzymes involved in cell wall and molybdenum cofactor biosynthesis, respectively, as targets responsible for the activity of TCA1. These in vitro and in vivo results indicate that this compound functions by a unique mechanism and suggest that TCA1 may lead to the development of a class of antituberculosis agents.

Details

Original languageEnglish
Pages (from-to)E2510-E2517
JournalNational Academy of Sciences. Proceedings
Volume110
Issue number27
Early online date17 Jun 2013
Publication statusPublished - 17 Jun 2013