High content screening identifies decaprenyl-phosphoribose 2' epimerase as a target for intracellular antimycobacterial inhibitors.

A critical feature of Mycobacterium tuberculosis, the causative agent of human tuberculosis (TB), is its ability to survive and multiply within macrophages, making these host cells an ideal niche for persisting microbes. Killing the intracellular tubercle bacilli is a key requirement for efficient t...

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Autores principales:	Thierry Christophe, Mary Jackson, Hee Kyoung Jeon, Denis Fenistein, Monica Contreras-Dominguez, Jaeseung Kim, Auguste Genovesio, Jean-Philippe Carralot, Fanny Ewann, Eun Hye Kim, Sae Yeon Lee, Sunhee Kang, Min Jung Seo, Eun Jung Park, Henrieta Skovierová, Ha Pham, Giovanna Riccardi, Ji Youn Nam, Laurent Marsollier, Marie Kempf, Marie-Laure Joly-Guillou, Taegwon Oh, Won Kyung Shin, Zaesung No, Ulf Nehrbass, Roland Brosch, Stewart T Cole, Priscille Brodin
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2009
Materias:	Immunologic diseases. Allergy RC581-607 Biology (General) QH301-705.5
Acceso en línea:	https://doaj.org/article/99417d33f11047f2814f85afb272f7e0
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spelling	oai:doaj.org-article:99417d33f11047f2814f85afb272f7e02021-11-25T05:48:32ZHigh content screening identifies decaprenyl-phosphoribose 2' epimerase as a target for intracellular antimycobacterial inhibitors.1553-73661553-737410.1371/journal.ppat.1000645https://doaj.org/article/99417d33f11047f2814f85afb272f7e02009-10-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/19876393/?tool=EBIhttps://doaj.org/toc/1553-7366https://doaj.org/toc/1553-7374A critical feature of Mycobacterium tuberculosis, the causative agent of human tuberculosis (TB), is its ability to survive and multiply within macrophages, making these host cells an ideal niche for persisting microbes. Killing the intracellular tubercle bacilli is a key requirement for efficient tuberculosis treatment, yet identifying potent inhibitors has been hampered by labor-intensive techniques and lack of validated targets. Here, we present the development of a phenotypic cell-based assay that uses automated confocal fluorescence microscopy for high throughput screening of chemicals that interfere with the replication of M. tuberculosis within macrophages. Screening a library of 57,000 small molecules led to the identification of 135 active compounds with potent intracellular anti-mycobacterial efficacy and no host cell toxicity. Among these, the dinitrobenzamide derivatives (DNB) showed high activity against M. tuberculosis, including extensively drug resistant (XDR) strains. More importantly, we demonstrate that incubation of M. tuberculosis with DNB inhibited the formation of both lipoarabinomannan and arabinogalactan, attributable to the inhibition of decaprenyl-phospho-arabinose synthesis catalyzed by the decaprenyl-phosphoribose 2' epimerase DprE1/DprE2. Inhibition of this new target will likely contribute to new therapeutic solutions against emerging XDR-TB. Beyond validating the high throughput/content screening approach, our results open new avenues for finding the next generation of antimicrobials.Thierry ChristopheMary JacksonHee Kyoung JeonDenis FenisteinMonica Contreras-DominguezJaeseung KimAuguste GenovesioJean-Philippe CarralotFanny EwannEun Hye KimSae Yeon LeeSunhee KangMin Jung SeoEun Jung ParkHenrieta SkovierováHa PhamGiovanna RiccardiJi Youn NamLaurent MarsollierMarie KempfMarie-Laure Joly-GuillouTaegwon OhWon Kyung ShinZaesung NoUlf NehrbassRoland BroschStewart T ColePriscille BrodinPublic Library of Science (PLoS)articleImmunologic diseases. AllergyRC581-607Biology (General)QH301-705.5ENPLoS Pathogens, Vol 5, Iss 10, p e1000645 (2009)
institution	DOAJ
collection	DOAJ
language	EN
topic	Immunologic diseases. Allergy RC581-607 Biology (General) QH301-705.5
spellingShingle	Immunologic diseases. Allergy RC581-607 Biology (General) QH301-705.5 Thierry Christophe Mary Jackson Hee Kyoung Jeon Denis Fenistein Monica Contreras-Dominguez Jaeseung Kim Auguste Genovesio Jean-Philippe Carralot Fanny Ewann Eun Hye Kim Sae Yeon Lee Sunhee Kang Min Jung Seo Eun Jung Park Henrieta Skovierová Ha Pham Giovanna Riccardi Ji Youn Nam Laurent Marsollier Marie Kempf Marie-Laure Joly-Guillou Taegwon Oh Won Kyung Shin Zaesung No Ulf Nehrbass Roland Brosch Stewart T Cole Priscille Brodin High content screening identifies decaprenyl-phosphoribose 2' epimerase as a target for intracellular antimycobacterial inhibitors.
description	A critical feature of Mycobacterium tuberculosis, the causative agent of human tuberculosis (TB), is its ability to survive and multiply within macrophages, making these host cells an ideal niche for persisting microbes. Killing the intracellular tubercle bacilli is a key requirement for efficient tuberculosis treatment, yet identifying potent inhibitors has been hampered by labor-intensive techniques and lack of validated targets. Here, we present the development of a phenotypic cell-based assay that uses automated confocal fluorescence microscopy for high throughput screening of chemicals that interfere with the replication of M. tuberculosis within macrophages. Screening a library of 57,000 small molecules led to the identification of 135 active compounds with potent intracellular anti-mycobacterial efficacy and no host cell toxicity. Among these, the dinitrobenzamide derivatives (DNB) showed high activity against M. tuberculosis, including extensively drug resistant (XDR) strains. More importantly, we demonstrate that incubation of M. tuberculosis with DNB inhibited the formation of both lipoarabinomannan and arabinogalactan, attributable to the inhibition of decaprenyl-phospho-arabinose synthesis catalyzed by the decaprenyl-phosphoribose 2' epimerase DprE1/DprE2. Inhibition of this new target will likely contribute to new therapeutic solutions against emerging XDR-TB. Beyond validating the high throughput/content screening approach, our results open new avenues for finding the next generation of antimicrobials.
format	article
author	Thierry Christophe Mary Jackson Hee Kyoung Jeon Denis Fenistein Monica Contreras-Dominguez Jaeseung Kim Auguste Genovesio Jean-Philippe Carralot Fanny Ewann Eun Hye Kim Sae Yeon Lee Sunhee Kang Min Jung Seo Eun Jung Park Henrieta Skovierová Ha Pham Giovanna Riccardi Ji Youn Nam Laurent Marsollier Marie Kempf Marie-Laure Joly-Guillou Taegwon Oh Won Kyung Shin Zaesung No Ulf Nehrbass Roland Brosch Stewart T Cole Priscille Brodin
author_facet	Thierry Christophe Mary Jackson Hee Kyoung Jeon Denis Fenistein Monica Contreras-Dominguez Jaeseung Kim Auguste Genovesio Jean-Philippe Carralot Fanny Ewann Eun Hye Kim Sae Yeon Lee Sunhee Kang Min Jung Seo Eun Jung Park Henrieta Skovierová Ha Pham Giovanna Riccardi Ji Youn Nam Laurent Marsollier Marie Kempf Marie-Laure Joly-Guillou Taegwon Oh Won Kyung Shin Zaesung No Ulf Nehrbass Roland Brosch Stewart T Cole Priscille Brodin
author_sort	Thierry Christophe
title	High content screening identifies decaprenyl-phosphoribose 2' epimerase as a target for intracellular antimycobacterial inhibitors.
title_short	High content screening identifies decaprenyl-phosphoribose 2' epimerase as a target for intracellular antimycobacterial inhibitors.
title_full	High content screening identifies decaprenyl-phosphoribose 2' epimerase as a target for intracellular antimycobacterial inhibitors.
title_fullStr	High content screening identifies decaprenyl-phosphoribose 2' epimerase as a target for intracellular antimycobacterial inhibitors.
title_full_unstemmed	High content screening identifies decaprenyl-phosphoribose 2' epimerase as a target for intracellular antimycobacterial inhibitors.
title_sort	high content screening identifies decaprenyl-phosphoribose 2' epimerase as a target for intracellular antimycobacterial inhibitors.
publisher	Public Library of Science (PLoS)
publishDate	2009
url	https://doaj.org/article/99417d33f11047f2814f85afb272f7e0
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High content screening identifies decaprenyl-phosphoribose 2' epimerase as a target for intracellular antimycobacterial inhibitors.

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