TgPRELID, a Mitochondrial Protein Linked to Multidrug Resistance in the Parasite <named-content content-type="genus-species">Toxoplasma gondii</named-content>

ABSTRACT New drugs to control infection with the protozoan parasite Toxoplasma gondii are needed as current treatments exert toxic side effects on patients. Approaches to develop novel compounds for drug development include screening of compound libraries and targeted inhibition of essential cellula...

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Autores principales:	Victoria Jeffers, Edwin T. Kamau, Ananth R. Srinivasan, Jonathan Harper, Preethi Sankaran, Sarah E. Post, Joseph M. Varberg, William J. Sullivan, Jon P. Boyle
Formato:	article
Lenguaje:	EN
Publicado:	American Society for Microbiology 2017
Materias:	PRELI domain Toxoplasma gondii mitochondrial protein import multidrug resistance Microbiology QR1-502
Acceso en línea:	https://doaj.org/article/b3da351a960c48d3b9fbeae40b5dad3a
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spelling	oai:doaj.org-article:b3da351a960c48d3b9fbeae40b5dad3a2021-11-15T15:22:03ZTgPRELID, a Mitochondrial Protein Linked to Multidrug Resistance in the Parasite <named-content content-type="genus-species">Toxoplasma gondii</named-content>10.1128/mSphere.00229-162379-5042https://doaj.org/article/b3da351a960c48d3b9fbeae40b5dad3a2017-02-01T00:00:00Zhttps://journals.asm.org/doi/10.1128/mSphere.00229-16https://doaj.org/toc/2379-5042ABSTRACT New drugs to control infection with the protozoan parasite Toxoplasma gondii are needed as current treatments exert toxic side effects on patients. Approaches to develop novel compounds for drug development include screening of compound libraries and targeted inhibition of essential cellular pathways. We identified two distinct compounds that display inhibitory activity against the parasite’s replicative stage: F3215-0002, which we previously identified during a compound library screen, and I-BET151, an inhibitor of bromodomains, the “reader” module of acetylated lysines. In independent studies, we sought to determine the targets of these two compounds using forward genetics, generating resistant mutants and identifying the determinants of resistance with comparative genome sequencing. Despite the dissimilarity of the two compounds, we recovered resistant mutants with nonsynonymous mutations in the same domain of the same gene, TGGT1_254250, which we found encodes a protein that localizes to the parasite mitochondrion (designated TgPRELID after the name of said domain). We found that mutants selected with one compound were cross resistant to the other compound, suggesting a common mechanism of resistance. To further support our hypothesis that TgPRELID mutations facilitate resistance to both I-BET151 and F3215-0002, CRISPR (clustered regularly interspaced short palindromic repeat)/CAS9-mediated mutation of TgPRELID directly led to increased F3215-0002 resistance. Finally, all resistance mutations clustered in the same subdomain of TgPRELID. These findings suggest that TgPRELID may encode a multidrug resistance factor or that I-BET151 and F3215-0002 have the same target(s) despite their distinct chemical structures. IMPORTANCE We report the discovery of TgPRELID, a previously uncharacterized mitochondrial protein linked to multidrug resistance in the parasite Toxoplasma gondii. Drug resistance remains a major problem in the battle against parasitic infection, and understanding how TgPRELID mutations augment resistance to multiple, distinct compounds will reveal needed insights into the development of new therapies for toxoplasmosis and other related parasitic diseases.Victoria JeffersEdwin T. KamauAnanth R. SrinivasanJonathan HarperPreethi SankaranSarah E. PostJoseph M. VarbergWilliam J. SullivanJon P. BoyleAmerican Society for MicrobiologyarticlePRELI domainToxoplasma gondiimitochondrial protein importmultidrug resistanceMicrobiologyQR1-502ENmSphere, Vol 2, Iss 1 (2017)
institution	DOAJ
collection	DOAJ
language	EN
topic	PRELI domain Toxoplasma gondii mitochondrial protein import multidrug resistance Microbiology QR1-502
spellingShingle	PRELI domain Toxoplasma gondii mitochondrial protein import multidrug resistance Microbiology QR1-502 Victoria Jeffers Edwin T. Kamau Ananth R. Srinivasan Jonathan Harper Preethi Sankaran Sarah E. Post Joseph M. Varberg William J. Sullivan Jon P. Boyle TgPRELID, a Mitochondrial Protein Linked to Multidrug Resistance in the Parasite <named-content content-type="genus-species">Toxoplasma gondii</named-content>
description	ABSTRACT New drugs to control infection with the protozoan parasite Toxoplasma gondii are needed as current treatments exert toxic side effects on patients. Approaches to develop novel compounds for drug development include screening of compound libraries and targeted inhibition of essential cellular pathways. We identified two distinct compounds that display inhibitory activity against the parasite’s replicative stage: F3215-0002, which we previously identified during a compound library screen, and I-BET151, an inhibitor of bromodomains, the “reader” module of acetylated lysines. In independent studies, we sought to determine the targets of these two compounds using forward genetics, generating resistant mutants and identifying the determinants of resistance with comparative genome sequencing. Despite the dissimilarity of the two compounds, we recovered resistant mutants with nonsynonymous mutations in the same domain of the same gene, TGGT1_254250, which we found encodes a protein that localizes to the parasite mitochondrion (designated TgPRELID after the name of said domain). We found that mutants selected with one compound were cross resistant to the other compound, suggesting a common mechanism of resistance. To further support our hypothesis that TgPRELID mutations facilitate resistance to both I-BET151 and F3215-0002, CRISPR (clustered regularly interspaced short palindromic repeat)/CAS9-mediated mutation of TgPRELID directly led to increased F3215-0002 resistance. Finally, all resistance mutations clustered in the same subdomain of TgPRELID. These findings suggest that TgPRELID may encode a multidrug resistance factor or that I-BET151 and F3215-0002 have the same target(s) despite their distinct chemical structures. IMPORTANCE We report the discovery of TgPRELID, a previously uncharacterized mitochondrial protein linked to multidrug resistance in the parasite Toxoplasma gondii. Drug resistance remains a major problem in the battle against parasitic infection, and understanding how TgPRELID mutations augment resistance to multiple, distinct compounds will reveal needed insights into the development of new therapies for toxoplasmosis and other related parasitic diseases.
format	article
author	Victoria Jeffers Edwin T. Kamau Ananth R. Srinivasan Jonathan Harper Preethi Sankaran Sarah E. Post Joseph M. Varberg William J. Sullivan Jon P. Boyle
author_facet	Victoria Jeffers Edwin T. Kamau Ananth R. Srinivasan Jonathan Harper Preethi Sankaran Sarah E. Post Joseph M. Varberg William J. Sullivan Jon P. Boyle
author_sort	Victoria Jeffers
title	TgPRELID, a Mitochondrial Protein Linked to Multidrug Resistance in the Parasite <named-content content-type="genus-species">Toxoplasma gondii</named-content>
title_short	TgPRELID, a Mitochondrial Protein Linked to Multidrug Resistance in the Parasite <named-content content-type="genus-species">Toxoplasma gondii</named-content>
title_full	TgPRELID, a Mitochondrial Protein Linked to Multidrug Resistance in the Parasite <named-content content-type="genus-species">Toxoplasma gondii</named-content>
title_fullStr	TgPRELID, a Mitochondrial Protein Linked to Multidrug Resistance in the Parasite <named-content content-type="genus-species">Toxoplasma gondii</named-content>
title_full_unstemmed	TgPRELID, a Mitochondrial Protein Linked to Multidrug Resistance in the Parasite <named-content content-type="genus-species">Toxoplasma gondii</named-content>
title_sort	tgprelid, a mitochondrial protein linked to multidrug resistance in the parasite <named-content content-type="genus-species">toxoplasma gondii</named-content>
publisher	American Society for Microbiology
publishDate	2017
url	https://doaj.org/article/b3da351a960c48d3b9fbeae40b5dad3a
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TgPRELID, a Mitochondrial Protein Linked to Multidrug Resistance in the Parasite <named-content content-type="genus-species">Toxoplasma gondii</named-content>

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