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 Mikusova; Gurdyal S. Besra; Klaus Fütterer; William R. Jacobs; Peter G. Schultz

doi:10.1073/pnas.1309171110

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

Microbiology & Immunology

Research output: Contribution to journal › Article › peer-review

186 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 language	English (US)
Pages (from-to)	E2510-E2517
Journal	Proceedings of the National Academy of Sciences of the United States of America
Volume	110
Issue number	27
DOIs	https://doi.org/10.1073/pnas.1309171110
State	Published - Jul 2 2013

Keywords

Drug resistance
Dual mechanism

ASJC Scopus subject areas

General

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1073/pnas.1309171110

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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

Wang, F, Sambandan, D, Halder, R, Wang, J, Batt, SM, Weinrick, B, Ahmad, I, Yang, P, Zhang, Y, Kim, J, Hassani, M, Huszar, S, Trefzer, C, Ma, Z, Kaneko, T, Mdluli, KE, Franzblau, S, Chatterjee, AK, Johnson, K, Mikusova, K, Besra, GS, Fütterer, K, Jacobs, WR & Schultz, PG 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, vol. 110, no. 27, pp. E2510-E2517. https://doi.org/10.1073/pnas.1309171110

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AU - Sambandan, Dhinakaran

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AU - Weinrick, Brian

AU - Ahmad, Insha

AU - Yang, Pengyu

AU - Zhang, Yong

AU - Kim, John

AU - Hassani, Morad

AU - Huszar, Stanislav

AU - Trefzer, Claudia

AU - Ma, Zhenkun

AU - Kaneko, Takushi

AU - Mdluli, Khisi E.

AU - Franzblau, Scott

AU - Chatterjee, Arnab K.

AU - Johnson, Kai

AU - Mikusova, Katarina

AU - Besra, Gurdyal S.

AU - Fütterer, Klaus

AU - Jacobs, William R.

AU - Schultz, Peter G.

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

Abstract

Keywords

ASJC Scopus subject areas

UN SDGs

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