Discovery of uncompetitive inhibitors of SapM that compromise intracellular survival of Mycobacterium tuberculosis

Abstract SapM is a secreted virulence factor from Mycobacterium tuberculosis critical for pathogen survival and persistence inside the host. Its full potential as a target for tuberculosis treatment has not yet been exploited because of the lack of potent inhibitors available. By screening over 1500...

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Autores principales:	Paulina Fernández-Soto, Joshua Casulli, Danilo Solano-Castro, Pablo Rodríguez-Fernández, Thomas A. Jowitt, Mark A. Travis, Jennifer S. Cavet, Lydia Tabernero
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2021
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/5135dd571c544dfd9a33769cbc83fbac
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spelling	oai:doaj.org-article:5135dd571c544dfd9a33769cbc83fbac2021-12-02T14:20:34ZDiscovery of uncompetitive inhibitors of SapM that compromise intracellular survival of Mycobacterium tuberculosis10.1038/s41598-021-87117-x2045-2322https://doaj.org/article/5135dd571c544dfd9a33769cbc83fbac2021-04-01T00:00:00Zhttps://doi.org/10.1038/s41598-021-87117-xhttps://doaj.org/toc/2045-2322Abstract SapM is a secreted virulence factor from Mycobacterium tuberculosis critical for pathogen survival and persistence inside the host. Its full potential as a target for tuberculosis treatment has not yet been exploited because of the lack of potent inhibitors available. By screening over 1500 small molecules, we have identified new potent and selective inhibitors of SapM with an uncompetitive mechanism of inhibition. The best inhibitors share a trihydroxy-benzene moiety essential for activity. Importantly, the inhibitors significantly reduce mycobacterial burden in infected human macrophages at 1 µM, and they are selective with respect to other mycobacterial and human phosphatases. The best inhibitor also reduces intracellular burden of Francisella tularensis, which secretes the virulence factor AcpA, a homologue of SapM, with the same mechanism of catalysis and inhibition. Our findings demonstrate that inhibition of SapM with small molecule inhibitors is efficient in reducing intracellular mycobacterial survival in host macrophages and confirm SapM as a potential therapeutic target. These initial compounds have favourable physico-chemical properties and provide a basis for exploration towards the development of new tuberculosis treatments. The efficacy of a SapM inhibitor in reducing Francisella tularensis intracellular burden suggests the potential for developing broad-spectrum antivirulence agents to treat microbial infections.Paulina Fernández-SotoJoshua CasulliDanilo Solano-CastroPablo Rodríguez-FernándezThomas A. JowittMark A. TravisJennifer S. CavetLydia TaberneroNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 11, Iss 1, Pp 1-11 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Paulina Fernández-Soto Joshua Casulli Danilo Solano-Castro Pablo Rodríguez-Fernández Thomas A. Jowitt Mark A. Travis Jennifer S. Cavet Lydia Tabernero Discovery of uncompetitive inhibitors of SapM that compromise intracellular survival of Mycobacterium tuberculosis
description	Abstract SapM is a secreted virulence factor from Mycobacterium tuberculosis critical for pathogen survival and persistence inside the host. Its full potential as a target for tuberculosis treatment has not yet been exploited because of the lack of potent inhibitors available. By screening over 1500 small molecules, we have identified new potent and selective inhibitors of SapM with an uncompetitive mechanism of inhibition. The best inhibitors share a trihydroxy-benzene moiety essential for activity. Importantly, the inhibitors significantly reduce mycobacterial burden in infected human macrophages at 1 µM, and they are selective with respect to other mycobacterial and human phosphatases. The best inhibitor also reduces intracellular burden of Francisella tularensis, which secretes the virulence factor AcpA, a homologue of SapM, with the same mechanism of catalysis and inhibition. Our findings demonstrate that inhibition of SapM with small molecule inhibitors is efficient in reducing intracellular mycobacterial survival in host macrophages and confirm SapM as a potential therapeutic target. These initial compounds have favourable physico-chemical properties and provide a basis for exploration towards the development of new tuberculosis treatments. The efficacy of a SapM inhibitor in reducing Francisella tularensis intracellular burden suggests the potential for developing broad-spectrum antivirulence agents to treat microbial infections.
format	article
author	Paulina Fernández-Soto Joshua Casulli Danilo Solano-Castro Pablo Rodríguez-Fernández Thomas A. Jowitt Mark A. Travis Jennifer S. Cavet Lydia Tabernero
author_facet	Paulina Fernández-Soto Joshua Casulli Danilo Solano-Castro Pablo Rodríguez-Fernández Thomas A. Jowitt Mark A. Travis Jennifer S. Cavet Lydia Tabernero
author_sort	Paulina Fernández-Soto
title	Discovery of uncompetitive inhibitors of SapM that compromise intracellular survival of Mycobacterium tuberculosis
title_short	Discovery of uncompetitive inhibitors of SapM that compromise intracellular survival of Mycobacterium tuberculosis
title_full	Discovery of uncompetitive inhibitors of SapM that compromise intracellular survival of Mycobacterium tuberculosis
title_fullStr	Discovery of uncompetitive inhibitors of SapM that compromise intracellular survival of Mycobacterium tuberculosis
title_full_unstemmed	Discovery of uncompetitive inhibitors of SapM that compromise intracellular survival of Mycobacterium tuberculosis
title_sort	discovery of uncompetitive inhibitors of sapm that compromise intracellular survival of mycobacterium tuberculosis
publisher	Nature Portfolio
publishDate	2021
url	https://doaj.org/article/5135dd571c544dfd9a33769cbc83fbac
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Discovery of uncompetitive inhibitors of SapM that compromise intracellular survival of Mycobacterium tuberculosis

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