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

Feng Wang; Dhinakaran Sambandan; Rajkumar Halder; Jianing Wang; Sarah Batt; 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; Gurdyal Besra; Klaus Futterer; William R Jacobs Jr; 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 Batt, 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 MikusovaGurdyal Besra, Klaus Futterer, William R Jacobs Jr, Peter G Schultz

Biosciences

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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.

Original language	English
Pages (from-to)	E2510-E2517
Journal	National Academy of Sciences. Proceedings
Volume	110
Issue number	27
Early online date	17 Jun 2013
DOIs	https://doi.org/10.1073/pnas.1309171110
Publication status	Published - 17 Jun 2013

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10.1073/pnas.1309171110

Wang, F et al. PNAS 2013Submitted manuscript, 1.37 MB

http://www.pnas.org/content/early/2013/06/12/1309171110.long

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

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title = "Identification of a small molecule with activity against drug-resistant and persistent tuberculosis",

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.",

author = "Feng Wang and Dhinakaran Sambandan and Rajkumar Halder and Jianing Wang and Sarah Batt and Brian Weinrick and Insha Ahmad and Pengyu Yang and Yong Zhang and John Kim and Morad Hassani and Stanislav Huszar and Claudia Trefzer and Zhenkun Ma and Takushi Taneko and Khisi Mdluli and Scott Franzblau and Arnab Chatterjee and Kai Johnson and Katarina Mikusova and Gurdyal Besra and Klaus Futterer and {Jacobs Jr}, {William R} and Schultz, {Peter G}",

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doi = "10.1073/pnas.1309171110",

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Wang, F, Sambandan, D, Halder, R, Wang, J, Batt, S, Weinrick, B, Ahmad, I, Yang, P, Zhang, Y, Kim, J, Hassani, M, Huszar, S, Trefzer, C, Ma, Z, Taneko, T, Mdluli, K, Franzblau, S, Chatterjee, A, Johnson, K, Mikusova, K, Besra, G , Futterer, K, Jacobs Jr, WR & Schultz, PG 2013, 'Identification of a small molecule with activity against drug-resistant and persistent tuberculosis', National Academy of Sciences. Proceedings, vol. 110, no. 27, pp. E2510-E2517. https://doi.org/10.1073/pnas.1309171110

TY - JOUR

T1 - Identification of a small molecule with activity against drug-resistant and persistent tuberculosis

AU - Wang, Feng

AU - Sambandan, Dhinakaran

AU - Halder, Rajkumar

AU - Wang, Jianing

AU - Batt, Sarah

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 - Taneko, Takushi

AU - Mdluli, Khisi

AU - Franzblau, Scott

AU - Chatterjee, Arnab

AU - Johnson, Kai

AU - Mikusova, Katarina

AU - Besra, Gurdyal

AU - Futterer, Klaus

AU - Jacobs Jr, William R

AU - Schultz, Peter G

PY - 2013/6/17

Y1 - 2013/6/17

N2 - 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.

AB - 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.

U2 - 10.1073/pnas.1309171110

DO - 10.1073/pnas.1309171110

M3 - Article

C2 - 23776209

SN - 0027-8424

VL - 110

SP - E2510-E2517

JO - National Academy of Sciences. Proceedings

JF - National Academy of Sciences. Proceedings

IS - 27

ER -

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

Abstract

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