Drug Repurposing Screening Identifies Novel Compounds That Effectively Inhibit <named-content content-type="genus-species">Toxoplasma gondii</named-content> Growth

ABSTRACT The urgent need to develop new antimicrobial therapies has spawned the development of repurposing screens in which well-studied drugs and other types of compounds are tested for potential off-label uses. As a proof-of-principle screen to identify compounds effective against Toxoplasma gondi...

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Autores principales:	Ashley J. Dittmar, Allison A. Drozda, Ira J. Blader
Formato:	article
Lenguaje:	EN
Publicado:	American Society for Microbiology 2016
Materias:	drug screens apicomplexan parasites host-cell interactions intracellular pathogens pharmacology Microbiology QR1-502
Acceso en línea:	https://doaj.org/article/68a0da91145a4c1087ed6a47bd3ce8f8
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spelling	oai:doaj.org-article:68a0da91145a4c1087ed6a47bd3ce8f82021-11-15T15:21:22ZDrug Repurposing Screening Identifies Novel Compounds That Effectively Inhibit <named-content content-type="genus-species">Toxoplasma gondii</named-content> Growth10.1128/mSphere.00042-152379-5042https://doaj.org/article/68a0da91145a4c1087ed6a47bd3ce8f82016-04-01T00:00:00Zhttps://journals.asm.org/doi/10.1128/mSphere.00042-15https://doaj.org/toc/2379-5042ABSTRACT The urgent need to develop new antimicrobial therapies has spawned the development of repurposing screens in which well-studied drugs and other types of compounds are tested for potential off-label uses. As a proof-of-principle screen to identify compounds effective against Toxoplasma gondii, we screened a collection of 1,120 compounds for the ability to significantly reduce Toxoplasma replication. A total of 94 compounds blocked parasite replication with 50% inhibitory concentrations of <5 µM. A significant number of these compounds are established inhibitors of dopamine or estrogen signaling. Follow-up experiments with the dopamine receptor inhibitor pimozide revealed that the drug impacted both parasite invasion and replication but did so independently of inhibition of dopamine or other neurotransmitter receptor signaling. Tamoxifen, which is an established inhibitor of the estrogen receptor, also reduced parasite invasion and replication. Even though Toxoplasma can activate the estrogen receptor, tamoxifen inhibits parasite growth independently of this transcription factor. Tamoxifen is also a potent inducer of autophagy, and we find that the drug stimulates recruitment of the autophagy marker light chain 3-green fluorescent protein onto the membrane of the vacuolar compartment in which the parasite resides and replicates. In contrast to other antiparasitic drugs, including pimozide, tamoxifen treatment of infected cells leads to a time-dependent elimination of intracellular parasites. Taken together, these data suggest that tamoxifen restricts Toxoplasma growth by inducing xenophagy or autophagic destruction of this obligate intracellular parasite. IMPORTANCE There is an urgent need to develop new therapies to treat microbial infections, and the repurposing of well-characterized compounds is emerging as one approach to achieving this goal. Using the protozoan parasite Toxoplasma gondii, we screened a library of 1,120 compounds and identified several compounds with significant antiparasitic activities. Among these were pimozide and tamoxifen, which are well-characterized drugs prescribed to treat patients with psychiatric disorders and breast cancer, respectively. The mechanisms by which these compounds target these disorders are known, but we show here that these drugs kill Toxoplasma through novel pathways, highlighting the potential utility of off-target effects in the treatment of infectious diseases.Ashley J. DittmarAllison A. DrozdaIra J. BladerAmerican Society for Microbiologyarticledrug screensapicomplexan parasiteshost-cell interactionsintracellular pathogenspharmacologyMicrobiologyQR1-502ENmSphere, Vol 1, Iss 2 (2016)
institution	DOAJ
collection	DOAJ
language	EN
topic	drug screens apicomplexan parasites host-cell interactions intracellular pathogens pharmacology Microbiology QR1-502
spellingShingle	drug screens apicomplexan parasites host-cell interactions intracellular pathogens pharmacology Microbiology QR1-502 Ashley J. Dittmar Allison A. Drozda Ira J. Blader Drug Repurposing Screening Identifies Novel Compounds That Effectively Inhibit <named-content content-type="genus-species">Toxoplasma gondii</named-content> Growth
description	ABSTRACT The urgent need to develop new antimicrobial therapies has spawned the development of repurposing screens in which well-studied drugs and other types of compounds are tested for potential off-label uses. As a proof-of-principle screen to identify compounds effective against Toxoplasma gondii, we screened a collection of 1,120 compounds for the ability to significantly reduce Toxoplasma replication. A total of 94 compounds blocked parasite replication with 50% inhibitory concentrations of <5 µM. A significant number of these compounds are established inhibitors of dopamine or estrogen signaling. Follow-up experiments with the dopamine receptor inhibitor pimozide revealed that the drug impacted both parasite invasion and replication but did so independently of inhibition of dopamine or other neurotransmitter receptor signaling. Tamoxifen, which is an established inhibitor of the estrogen receptor, also reduced parasite invasion and replication. Even though Toxoplasma can activate the estrogen receptor, tamoxifen inhibits parasite growth independently of this transcription factor. Tamoxifen is also a potent inducer of autophagy, and we find that the drug stimulates recruitment of the autophagy marker light chain 3-green fluorescent protein onto the membrane of the vacuolar compartment in which the parasite resides and replicates. In contrast to other antiparasitic drugs, including pimozide, tamoxifen treatment of infected cells leads to a time-dependent elimination of intracellular parasites. Taken together, these data suggest that tamoxifen restricts Toxoplasma growth by inducing xenophagy or autophagic destruction of this obligate intracellular parasite. IMPORTANCE There is an urgent need to develop new therapies to treat microbial infections, and the repurposing of well-characterized compounds is emerging as one approach to achieving this goal. Using the protozoan parasite Toxoplasma gondii, we screened a library of 1,120 compounds and identified several compounds with significant antiparasitic activities. Among these were pimozide and tamoxifen, which are well-characterized drugs prescribed to treat patients with psychiatric disorders and breast cancer, respectively. The mechanisms by which these compounds target these disorders are known, but we show here that these drugs kill Toxoplasma through novel pathways, highlighting the potential utility of off-target effects in the treatment of infectious diseases.
format	article
author	Ashley J. Dittmar Allison A. Drozda Ira J. Blader
author_facet	Ashley J. Dittmar Allison A. Drozda Ira J. Blader
author_sort	Ashley J. Dittmar
title	Drug Repurposing Screening Identifies Novel Compounds That Effectively Inhibit <named-content content-type="genus-species">Toxoplasma gondii</named-content> Growth
title_short	Drug Repurposing Screening Identifies Novel Compounds That Effectively Inhibit <named-content content-type="genus-species">Toxoplasma gondii</named-content> Growth
title_full	Drug Repurposing Screening Identifies Novel Compounds That Effectively Inhibit <named-content content-type="genus-species">Toxoplasma gondii</named-content> Growth
title_fullStr	Drug Repurposing Screening Identifies Novel Compounds That Effectively Inhibit <named-content content-type="genus-species">Toxoplasma gondii</named-content> Growth
title_full_unstemmed	Drug Repurposing Screening Identifies Novel Compounds That Effectively Inhibit <named-content content-type="genus-species">Toxoplasma gondii</named-content> Growth
title_sort	drug repurposing screening identifies novel compounds that effectively inhibit <named-content content-type="genus-species">toxoplasma gondii</named-content> growth
publisher	American Society for Microbiology
publishDate	2016
url	https://doaj.org/article/68a0da91145a4c1087ed6a47bd3ce8f8
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Drug Repurposing Screening Identifies Novel Compounds That Effectively Inhibit <named-content content-type="genus-species">Toxoplasma gondii</named-content> Growth

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