Repurposing diphenylbutylpiperidine-class antipsychotic drugs for host-directed therapy of Mycobacterium tuberculosis and Salmonella enterica infections

Abstract The persistent increase of multidrug-resistant (MDR) Mycobacterium tuberculosis (Mtb) infections negatively impacts Tuberculosis treatment outcomes. Host-directed therapies (HDT) pose an complementing strategy, particularly since Mtb is highly successful in evading host-defense by manipulat...

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Autores principales:	M. T. Heemskerk, C. J. Korbee, J. J. Esselink, C. Carvalho dos Santos, S. van Veen, I. F. Gordijn, F. Vrieling, K. V. Walburg, C. G. Engele, K. Dijkman, L. Wilson, F. A. W. Verreck, T. H. M. Ottenhoff, M. C. Haks
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2021
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/1ec152b467db4abebb49dc8f7a4e9c3c
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spelling	oai:doaj.org-article:1ec152b467db4abebb49dc8f7a4e9c3c2021-12-02T18:37:10ZRepurposing diphenylbutylpiperidine-class antipsychotic drugs for host-directed therapy of Mycobacterium tuberculosis and Salmonella enterica infections10.1038/s41598-021-98980-z2045-2322https://doaj.org/article/1ec152b467db4abebb49dc8f7a4e9c3c2021-10-01T00:00:00Zhttps://doi.org/10.1038/s41598-021-98980-zhttps://doaj.org/toc/2045-2322Abstract The persistent increase of multidrug-resistant (MDR) Mycobacterium tuberculosis (Mtb) infections negatively impacts Tuberculosis treatment outcomes. Host-directed therapies (HDT) pose an complementing strategy, particularly since Mtb is highly successful in evading host-defense by manipulating host-signaling pathways. Here, we screened a library containing autophagy-modulating compounds for their ability to inhibit intracellular Mtb-bacteria. Several active compounds were identified, including two drugs of the diphenylbutylpiperidine-class, Fluspirilene and Pimozide, commonly used as antipsychotics. Both molecules inhibited intracellular Mtb in pro- as well as anti-inflammatory primary human macrophages in a host-directed manner and synergized with conventional anti-bacterials. Importantly, these inhibitory effects extended to MDR-Mtb strains and the unrelated intracellular pathogen, Salmonella enterica serovar Typhimurium (Stm). Mechanistically Fluspirilene and Pimozide were shown to regulate autophagy and alter the lysosomal response, partly correlating with increased bacterial localization to autophago(lyso)somes. Pimozide’s and Fluspirilene’s efficacy was inhibited by antioxidants, suggesting involvement of the oxidative-stress response in Mtb growth control. Furthermore, Fluspirilene and especially Pimozide counteracted Mtb-induced STAT5 phosphorylation, thereby reducing Mtb phagosome-localized CISH that promotes phagosomal acidification. In conclusion, two approved antipsychotic drugs, Pimozide and Fluspirilene, constitute highly promising and rapidly translatable candidates for HDT against Mtb and Stm and act by modulating the autophagic/lysosomal response by multiple mechanisms.M. T. HeemskerkC. J. KorbeeJ. J. EsselinkC. Carvalho dos SantosS. van VeenI. F. GordijnF. VrielingK. V. WalburgC. G. EngeleK. DijkmanL. WilsonF. A. W. VerreckT. H. M. OttenhoffM. C. HaksNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 11, Iss 1, Pp 1-18 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q M. T. Heemskerk C. J. Korbee J. J. Esselink C. Carvalho dos Santos S. van Veen I. F. Gordijn F. Vrieling K. V. Walburg C. G. Engele K. Dijkman L. Wilson F. A. W. Verreck T. H. M. Ottenhoff M. C. Haks Repurposing diphenylbutylpiperidine-class antipsychotic drugs for host-directed therapy of Mycobacterium tuberculosis and Salmonella enterica infections
description	Abstract The persistent increase of multidrug-resistant (MDR) Mycobacterium tuberculosis (Mtb) infections negatively impacts Tuberculosis treatment outcomes. Host-directed therapies (HDT) pose an complementing strategy, particularly since Mtb is highly successful in evading host-defense by manipulating host-signaling pathways. Here, we screened a library containing autophagy-modulating compounds for their ability to inhibit intracellular Mtb-bacteria. Several active compounds were identified, including two drugs of the diphenylbutylpiperidine-class, Fluspirilene and Pimozide, commonly used as antipsychotics. Both molecules inhibited intracellular Mtb in pro- as well as anti-inflammatory primary human macrophages in a host-directed manner and synergized with conventional anti-bacterials. Importantly, these inhibitory effects extended to MDR-Mtb strains and the unrelated intracellular pathogen, Salmonella enterica serovar Typhimurium (Stm). Mechanistically Fluspirilene and Pimozide were shown to regulate autophagy and alter the lysosomal response, partly correlating with increased bacterial localization to autophago(lyso)somes. Pimozide’s and Fluspirilene’s efficacy was inhibited by antioxidants, suggesting involvement of the oxidative-stress response in Mtb growth control. Furthermore, Fluspirilene and especially Pimozide counteracted Mtb-induced STAT5 phosphorylation, thereby reducing Mtb phagosome-localized CISH that promotes phagosomal acidification. In conclusion, two approved antipsychotic drugs, Pimozide and Fluspirilene, constitute highly promising and rapidly translatable candidates for HDT against Mtb and Stm and act by modulating the autophagic/lysosomal response by multiple mechanisms.
format	article
author	M. T. Heemskerk C. J. Korbee J. J. Esselink C. Carvalho dos Santos S. van Veen I. F. Gordijn F. Vrieling K. V. Walburg C. G. Engele K. Dijkman L. Wilson F. A. W. Verreck T. H. M. Ottenhoff M. C. Haks
author_facet	M. T. Heemskerk C. J. Korbee J. J. Esselink C. Carvalho dos Santos S. van Veen I. F. Gordijn F. Vrieling K. V. Walburg C. G. Engele K. Dijkman L. Wilson F. A. W. Verreck T. H. M. Ottenhoff M. C. Haks
author_sort	M. T. Heemskerk
title	Repurposing diphenylbutylpiperidine-class antipsychotic drugs for host-directed therapy of Mycobacterium tuberculosis and Salmonella enterica infections
title_short	Repurposing diphenylbutylpiperidine-class antipsychotic drugs for host-directed therapy of Mycobacterium tuberculosis and Salmonella enterica infections
title_full	Repurposing diphenylbutylpiperidine-class antipsychotic drugs for host-directed therapy of Mycobacterium tuberculosis and Salmonella enterica infections
title_fullStr	Repurposing diphenylbutylpiperidine-class antipsychotic drugs for host-directed therapy of Mycobacterium tuberculosis and Salmonella enterica infections
title_full_unstemmed	Repurposing diphenylbutylpiperidine-class antipsychotic drugs for host-directed therapy of Mycobacterium tuberculosis and Salmonella enterica infections
title_sort	repurposing diphenylbutylpiperidine-class antipsychotic drugs for host-directed therapy of mycobacterium tuberculosis and salmonella enterica infections
publisher	Nature Portfolio
publishDate	2021
url	https://doaj.org/article/1ec152b467db4abebb49dc8f7a4e9c3c
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Repurposing diphenylbutylpiperidine-class antipsychotic drugs for host-directed therapy of Mycobacterium tuberculosis and Salmonella enterica infections

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