Antimycobacterial drug discovery using Mycobacteria-infected amoebae identifies anti-infectives and new molecular targets

Abstract Tuberculosis remains a serious threat to human health world-wide, and improved efficiency of medical treatment requires a better understanding of the pathogenesis and the discovery of new drugs. In the present study, we performed a whole-cell based screen in order to complete the characteri...

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Autores principales:	Valentin Trofimov, Sébastien Kicka, Sabrina Mucaria, Nabil Hanna, Fernando Ramon-Olayo, Laura Vela-Gonzalez Del Peral, Joël Lelièvre, Lluís Ballell, Leonardo Scapozza, Gurdyal S. Besra, Jonathan A. G. Cox, Thierry Soldati
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2018
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/083087377a9442d89e1c1d4ec18b7f01
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spelling	oai:doaj.org-article:083087377a9442d89e1c1d4ec18b7f012021-12-02T15:07:49ZAntimycobacterial drug discovery using Mycobacteria-infected amoebae identifies anti-infectives and new molecular targets10.1038/s41598-018-22228-62045-2322https://doaj.org/article/083087377a9442d89e1c1d4ec18b7f012018-03-01T00:00:00Zhttps://doi.org/10.1038/s41598-018-22228-6https://doaj.org/toc/2045-2322Abstract Tuberculosis remains a serious threat to human health world-wide, and improved efficiency of medical treatment requires a better understanding of the pathogenesis and the discovery of new drugs. In the present study, we performed a whole-cell based screen in order to complete the characterization of 168 compounds from the GlaxoSmithKline TB-set. We have established and utilized novel previously unexplored host-model systems to characterize the GSK compounds, i.e. the amoeboid organisms D. discoideum and A. castellanii, as well as a microglial phagocytic cell line, BV2. We infected these host cells with Mycobacterium marinum to monitor and characterize the anti-infective activity of the compounds with quantitative fluorescence measurements and high-content microscopy. In summary, 88.1% of the compounds were confirmed as antibiotics against M. marinum, 11.3% and 4.8% displayed strong anti-infective activity in, respectively, the mammalian and protozoan infection models. Additionally, in the two systems, 13–14% of the compounds displayed pro-infective activity. Our studies underline the relevance of using evolutionarily distant pathogen and host models in order to reveal conserved mechanisms of virulence and defence, respectively, which are potential “universal” targets for intervention. Subsequent mechanism of action studies based on generation of over-expresser M. bovis BCG strains, generation of spontaneous resistant mutants and whole genome sequencing revealed four new molecular targets, including FbpA, MurC, MmpL3 and GlpK.Valentin TrofimovSébastien KickaSabrina MucariaNabil HannaFernando Ramon-OlayoLaura Vela-Gonzalez Del PeralJoël LelièvreLluís BallellLeonardo ScapozzaGurdyal S. BesraJonathan A. G. CoxThierry SoldatiNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 8, Iss 1, Pp 1-15 (2018)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Valentin Trofimov Sébastien Kicka Sabrina Mucaria Nabil Hanna Fernando Ramon-Olayo Laura Vela-Gonzalez Del Peral Joël Lelièvre Lluís Ballell Leonardo Scapozza Gurdyal S. Besra Jonathan A. G. Cox Thierry Soldati Antimycobacterial drug discovery using Mycobacteria-infected amoebae identifies anti-infectives and new molecular targets
description	Abstract Tuberculosis remains a serious threat to human health world-wide, and improved efficiency of medical treatment requires a better understanding of the pathogenesis and the discovery of new drugs. In the present study, we performed a whole-cell based screen in order to complete the characterization of 168 compounds from the GlaxoSmithKline TB-set. We have established and utilized novel previously unexplored host-model systems to characterize the GSK compounds, i.e. the amoeboid organisms D. discoideum and A. castellanii, as well as a microglial phagocytic cell line, BV2. We infected these host cells with Mycobacterium marinum to monitor and characterize the anti-infective activity of the compounds with quantitative fluorescence measurements and high-content microscopy. In summary, 88.1% of the compounds were confirmed as antibiotics against M. marinum, 11.3% and 4.8% displayed strong anti-infective activity in, respectively, the mammalian and protozoan infection models. Additionally, in the two systems, 13–14% of the compounds displayed pro-infective activity. Our studies underline the relevance of using evolutionarily distant pathogen and host models in order to reveal conserved mechanisms of virulence and defence, respectively, which are potential “universal” targets for intervention. Subsequent mechanism of action studies based on generation of over-expresser M. bovis BCG strains, generation of spontaneous resistant mutants and whole genome sequencing revealed four new molecular targets, including FbpA, MurC, MmpL3 and GlpK.
format	article
author	Valentin Trofimov Sébastien Kicka Sabrina Mucaria Nabil Hanna Fernando Ramon-Olayo Laura Vela-Gonzalez Del Peral Joël Lelièvre Lluís Ballell Leonardo Scapozza Gurdyal S. Besra Jonathan A. G. Cox Thierry Soldati
author_facet	Valentin Trofimov Sébastien Kicka Sabrina Mucaria Nabil Hanna Fernando Ramon-Olayo Laura Vela-Gonzalez Del Peral Joël Lelièvre Lluís Ballell Leonardo Scapozza Gurdyal S. Besra Jonathan A. G. Cox Thierry Soldati
author_sort	Valentin Trofimov
title	Antimycobacterial drug discovery using Mycobacteria-infected amoebae identifies anti-infectives and new molecular targets
title_short	Antimycobacterial drug discovery using Mycobacteria-infected amoebae identifies anti-infectives and new molecular targets
title_full	Antimycobacterial drug discovery using Mycobacteria-infected amoebae identifies anti-infectives and new molecular targets
title_fullStr	Antimycobacterial drug discovery using Mycobacteria-infected amoebae identifies anti-infectives and new molecular targets
title_full_unstemmed	Antimycobacterial drug discovery using Mycobacteria-infected amoebae identifies anti-infectives and new molecular targets
title_sort	antimycobacterial drug discovery using mycobacteria-infected amoebae identifies anti-infectives and new molecular targets
publisher	Nature Portfolio
publishDate	2018
url	https://doaj.org/article/083087377a9442d89e1c1d4ec18b7f01
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Antimycobacterial drug discovery using Mycobacteria-infected amoebae identifies anti-infectives and new molecular targets

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