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

Feng Wang, Dhinakaran Sambandan, Rajkumar Halder, Jianing Wang, Sarah M. Batt, Brian Weinrick, Insha Ahmad, Pengyu Yang, Yong Zhang, John Kim, Morad Hassani, Stanislav Huszar, Claudia Trefzer, Zhenkun Ma, Takushi Kaneko, Khisi E. Mdluli, Scott Franzblau, Arnab K. Chatterjee, Kai Johnson, Katarina MikusovaGurdyal S. Besra, Klaus Fütterer, William R. Jacobs, Peter G. Schultz

Research output: Contribution to journalArticle

121 Scopus citations

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 decaprenylphosphoryl-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.

Original languageEnglish (US)
Pages (from-to)E2510-E2517
JournalProceedings of the National Academy of Sciences of the United States of America
Volume110
Issue number27
DOIs
StatePublished - Jul 2 2013

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Keywords

  • Drug resistance
  • Dual mechanism

ASJC Scopus subject areas

  • General

Cite this

Wang, F., Sambandan, D., Halder, R., Wang, J., Batt, S. M., Weinrick, B., Ahmad, I., Yang, P., Zhang, Y., Kim, J., Hassani, M., Huszar, S., Trefzer, C., Ma, Z., Kaneko, T., Mdluli, K. E., Franzblau, S., Chatterjee, A. K., Johnson, K., ... Schultz, P. G. (2013). Identification of a small molecule with activity against drug-resistant and persistent tuberculosis. Proceedings of the National Academy of Sciences of the United States of America, 110(27), E2510-E2517. https://doi.org/10.1073/pnas.1309171110