Targeting histone acetylation to overcome drug resistance in the parasite Trichomonas vaginalis

Autores
Seifert Gorzycki, Julieta Lara; Muñoz, Daniela; Lizarraga, Ayelen; Iriarte, Lucrecia Soledad; Cóceres, Verónica Mabel; Strobl Mazzulla, Pablo Hernán; de Miguel, Natalia
Año de publicación
2025
Idioma
inglés
Tipo de recurso
artículo
Estado
versión publicada
Descripción
Trichomoniasis, caused by the parasite Trichomonas vaginalis, is the most common non-viral sexually transmitted infection. Current treatment relies exclusively on 5-nitroimidazole drugs, with metronidazole (MTZ) as the primary option. However, the increasing prevalence of MTZ-resistant strains poses a significant challenge, particularly in the current absence of alternative therapies. Several studies have revealed that the development of metronidazole resistance in T. vaginalis is linked to genomic and transcriptional alterations. Given the role of epigenetic regulation in controlling gene expression, we investigated whether targeting histone deacetylase (HDAC) enzymes could influence drug resistance. Treatment of an MTZ-resistant strain (B7268) with the HDAC inhibitor, trichostatin A (TSA), in combination with MTZ enhanced drug sensitivity and induced significant genome-wide transcriptional changes, as revealed by RNA-seq analysis. To identify drug-related genes epigenetically silenced in the resistant strain but highly active in a sensitive strain, we compared the expression levels of the genes affected by TSA and MTZ treatment with their baseline expression profiles in both resistant and sensitive strains. This analysis identified 130 candidate genes differentially expressed in the sensitive strain NYH209, less expressed in the resistant B7268 strain, that exhibited significant expression changes upon TSA and MTZ treatment. Functional validation involved transfecting the B7268 strain with plasmids encoding four individual candidate genes: a thioredoxin reductase (TrxR), a cysteine synthase (CS), and two genes containing Myb domains (Myb5 and Myb6). Overexpression of three of these genes resulted in a marked reduction in MTZ resistance, demonstrating their role in modulating drug sensitivity. Our findings identified three novel genes that modulate drug resistance in T. vaginalis. This study reveals a previously unknown epigenetic mechanism underlying drug resistance and highlights the therapeutic potential of targeting epigenetic factors, such as HDACs, to overcome resistance and improve treatment efficacy.
Fil: Seifert Gorzycki, Julieta Lara. Universidad Nacional de San Martin. Instituto Tecnologico de Chascomus. - Consejo Nacional de Investigaciones Cientificas y Tecnicas. Centro Cientifico Tecnologico Conicet - la Plata. Instituto Tecnologico de Chascomus.; Argentina
Fil: Muñoz, Daniela. Universidad Nacional de San Martin. Instituto Tecnologico de Chascomus. - Consejo Nacional de Investigaciones Cientificas y Tecnicas. Centro Cientifico Tecnologico Conicet - la Plata. Instituto Tecnologico de Chascomus.; Argentina
Fil: Lizarraga, Ayelen. Universidad Nacional de San Martin. Instituto Tecnologico de Chascomus. - Consejo Nacional de Investigaciones Cientificas y Tecnicas. Centro Cientifico Tecnologico Conicet - la Plata. Instituto Tecnologico de Chascomus.; Argentina
Fil: Iriarte, Lucrecia Soledad. Universidad Nacional de San Martin. Instituto Tecnologico de Chascomus. - Consejo Nacional de Investigaciones Cientificas y Tecnicas. Centro Cientifico Tecnologico Conicet - la Plata. Instituto Tecnologico de Chascomus.; Argentina
Fil: Cóceres, Verónica Mabel. Universidad Nacional de San Martin. Instituto Tecnologico de Chascomus. - Consejo Nacional de Investigaciones Cientificas y Tecnicas. Centro Cientifico Tecnologico Conicet - la Plata. Instituto Tecnologico de Chascomus.; Argentina
Fil: Strobl Mazzulla, Pablo Hernán. Universidad Nacional de San Martin. Instituto Tecnologico de Chascomus. - Consejo Nacional de Investigaciones Cientificas y Tecnicas. Centro Cientifico Tecnologico Conicet - la Plata. Instituto Tecnologico de Chascomus.; Argentina
Fil: de Miguel, Natalia. Universidad Nacional de San Martin. Instituto Tecnologico de Chascomus. - Consejo Nacional de Investigaciones Cientificas y Tecnicas. Centro Cientifico Tecnologico Conicet - la Plata. Instituto Tecnologico de Chascomus.; Argentina
Materia
METRONIDAZOLE
EPIGENETIC
HISTONE ACETYLATION
DRUG RESISTANCE
Nivel de accesibilidad
acceso abierto
Condiciones de uso
https://creativecommons.org/licenses/by/2.5/ar/
Repositorio
CONICET Digital (CONICET)
Institución
Consejo Nacional de Investigaciones Científicas y Técnicas
OAI Identificador
oai:ri.conicet.gov.ar:11336/266739
Acceder
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oai_identifier_str oai:ri.conicet.gov.ar:11336/266739
network_acronym_str CONICETDig
repository_id_str 3498
network_name_str CONICET Digital (CONICET)
spelling Targeting histone acetylation to overcome drug resistance in the parasite Trichomonas vaginalisSeifert Gorzycki, Julieta LaraMuñoz, DanielaLizarraga, AyelenIriarte, Lucrecia SoledadCóceres, Verónica MabelStrobl Mazzulla, Pablo Hernánde Miguel, NataliaMETRONIDAZOLEEPIGENETICHISTONE ACETYLATIONDRUG RESISTANCEhttps://purl.org/becyt/ford/1.6https://purl.org/becyt/ford/1Trichomoniasis, caused by the parasite Trichomonas vaginalis, is the most common non-viral sexually transmitted infection. Current treatment relies exclusively on 5-nitroimidazole drugs, with metronidazole (MTZ) as the primary option. However, the increasing prevalence of MTZ-resistant strains poses a significant challenge, particularly in the current absence of alternative therapies. Several studies have revealed that the development of metronidazole resistance in T. vaginalis is linked to genomic and transcriptional alterations. Given the role of epigenetic regulation in controlling gene expression, we investigated whether targeting histone deacetylase (HDAC) enzymes could influence drug resistance. Treatment of an MTZ-resistant strain (B7268) with the HDAC inhibitor, trichostatin A (TSA), in combination with MTZ enhanced drug sensitivity and induced significant genome-wide transcriptional changes, as revealed by RNA-seq analysis. To identify drug-related genes epigenetically silenced in the resistant strain but highly active in a sensitive strain, we compared the expression levels of the genes affected by TSA and MTZ treatment with their baseline expression profiles in both resistant and sensitive strains. This analysis identified 130 candidate genes differentially expressed in the sensitive strain NYH209, less expressed in the resistant B7268 strain, that exhibited significant expression changes upon TSA and MTZ treatment. Functional validation involved transfecting the B7268 strain with plasmids encoding four individual candidate genes: a thioredoxin reductase (TrxR), a cysteine synthase (CS), and two genes containing Myb domains (Myb5 and Myb6). Overexpression of three of these genes resulted in a marked reduction in MTZ resistance, demonstrating their role in modulating drug sensitivity. Our findings identified three novel genes that modulate drug resistance in T. vaginalis. This study reveals a previously unknown epigenetic mechanism underlying drug resistance and highlights the therapeutic potential of targeting epigenetic factors, such as HDACs, to overcome resistance and improve treatment efficacy.Fil: Seifert Gorzycki, Julieta Lara. Universidad Nacional de San Martin. Instituto Tecnologico de Chascomus. - Consejo Nacional de Investigaciones Cientificas y Tecnicas. Centro Cientifico Tecnologico Conicet - la Plata. Instituto Tecnologico de Chascomus.; ArgentinaFil: Muñoz, Daniela. Universidad Nacional de San Martin. Instituto Tecnologico de Chascomus. - Consejo Nacional de Investigaciones Cientificas y Tecnicas. Centro Cientifico Tecnologico Conicet - la Plata. Instituto Tecnologico de Chascomus.; ArgentinaFil: Lizarraga, Ayelen. Universidad Nacional de San Martin. Instituto Tecnologico de Chascomus. - Consejo Nacional de Investigaciones Cientificas y Tecnicas. Centro Cientifico Tecnologico Conicet - la Plata. Instituto Tecnologico de Chascomus.; ArgentinaFil: Iriarte, Lucrecia Soledad. Universidad Nacional de San Martin. Instituto Tecnologico de Chascomus. - Consejo Nacional de Investigaciones Cientificas y Tecnicas. Centro Cientifico Tecnologico Conicet - la Plata. Instituto Tecnologico de Chascomus.; ArgentinaFil: Cóceres, Verónica Mabel. Universidad Nacional de San Martin. Instituto Tecnologico de Chascomus. - Consejo Nacional de Investigaciones Cientificas y Tecnicas. Centro Cientifico Tecnologico Conicet - la Plata. Instituto Tecnologico de Chascomus.; ArgentinaFil: Strobl Mazzulla, Pablo Hernán. Universidad Nacional de San Martin. Instituto Tecnologico de Chascomus. - Consejo Nacional de Investigaciones Cientificas y Tecnicas. Centro Cientifico Tecnologico Conicet - la Plata. Instituto Tecnologico de Chascomus.; ArgentinaFil: de Miguel, Natalia. Universidad Nacional de San Martin. Instituto Tecnologico de Chascomus. - Consejo Nacional de Investigaciones Cientificas y Tecnicas. Centro Cientifico Tecnologico Conicet - la Plata. Instituto Tecnologico de Chascomus.; ArgentinaCold Spring Harbor Laboratory Press2025-01info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionhttp://purl.org/coar/resource_type/c_6501info:ar-repo/semantics/articuloapplication/pdfapplication/pdfhttp://hdl.handle.net/11336/266739Seifert Gorzycki, Julieta Lara; Muñoz, Daniela; Lizarraga, Ayelen; Iriarte, Lucrecia Soledad; Cóceres, Verónica Mabel; et al.; Targeting histone acetylation to overcome drug resistance in the parasite Trichomonas vaginalis; Cold Spring Harbor Laboratory Press; BioRxiv; 2025; 1-2025; 1-292692-8205CONICET DigitalCONICETenginfo:eu-repo/semantics/altIdentifier/doi/10.1101/2025.01.07.631743info:eu-repo/semantics/altIdentifier/url/https://www.biorxiv.org/content/10.1101/2025.01.07.631743v1info:eu-repo/semantics/openAccesshttps://creativecommons.org/licenses/by/2.5/ar/reponame:CONICET Digital (CONICET)instname:Consejo Nacional de Investigaciones Científicas y Técnicas2025-09-29T09:42:39Zoai:ri.conicet.gov.ar:11336/266739instacron:CONICETInstitucionalhttp://ri.conicet.gov.ar/Organismo científico-tecnológicoNo correspondehttp://ri.conicet.gov.ar/oai/requestdasensio@conicet.gov.ar; lcarlino@conicet.gov.arArgentinaNo correspondeNo correspondeNo correspondeopendoar:34982025-09-29 09:42:39.955CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicasfalse
dc.title.none.fl_str_mv Targeting histone acetylation to overcome drug resistance in the parasite Trichomonas vaginalis
title Targeting histone acetylation to overcome drug resistance in the parasite Trichomonas vaginalis
spellingShingle Targeting histone acetylation to overcome drug resistance in the parasite Trichomonas vaginalis
Seifert Gorzycki, Julieta Lara
METRONIDAZOLE
EPIGENETIC
HISTONE ACETYLATION
DRUG RESISTANCE
title_short Targeting histone acetylation to overcome drug resistance in the parasite Trichomonas vaginalis
title_full Targeting histone acetylation to overcome drug resistance in the parasite Trichomonas vaginalis
title_fullStr Targeting histone acetylation to overcome drug resistance in the parasite Trichomonas vaginalis
title_full_unstemmed Targeting histone acetylation to overcome drug resistance in the parasite Trichomonas vaginalis
title_sort Targeting histone acetylation to overcome drug resistance in the parasite Trichomonas vaginalis
dc.creator.none.fl_str_mv Seifert Gorzycki, Julieta Lara
Muñoz, Daniela
Lizarraga, Ayelen
Iriarte, Lucrecia Soledad
Cóceres, Verónica Mabel
Strobl Mazzulla, Pablo Hernán
de Miguel, Natalia
author Seifert Gorzycki, Julieta Lara
author_facet Seifert Gorzycki, Julieta Lara
Muñoz, Daniela
Lizarraga, Ayelen
Iriarte, Lucrecia Soledad
Cóceres, Verónica Mabel
Strobl Mazzulla, Pablo Hernán
de Miguel, Natalia
author_role author
author2 Muñoz, Daniela
Lizarraga, Ayelen
Iriarte, Lucrecia Soledad
Cóceres, Verónica Mabel
Strobl Mazzulla, Pablo Hernán
de Miguel, Natalia
author2_role author
author
author
author
author
author
dc.subject.none.fl_str_mv METRONIDAZOLE
EPIGENETIC
HISTONE ACETYLATION
DRUG RESISTANCE
topic METRONIDAZOLE
EPIGENETIC
HISTONE ACETYLATION
DRUG RESISTANCE
purl_subject.fl_str_mv https://purl.org/becyt/ford/1.6
https://purl.org/becyt/ford/1
dc.description.none.fl_txt_mv Trichomoniasis, caused by the parasite Trichomonas vaginalis, is the most common non-viral sexually transmitted infection. Current treatment relies exclusively on 5-nitroimidazole drugs, with metronidazole (MTZ) as the primary option. However, the increasing prevalence of MTZ-resistant strains poses a significant challenge, particularly in the current absence of alternative therapies. Several studies have revealed that the development of metronidazole resistance in T. vaginalis is linked to genomic and transcriptional alterations. Given the role of epigenetic regulation in controlling gene expression, we investigated whether targeting histone deacetylase (HDAC) enzymes could influence drug resistance. Treatment of an MTZ-resistant strain (B7268) with the HDAC inhibitor, trichostatin A (TSA), in combination with MTZ enhanced drug sensitivity and induced significant genome-wide transcriptional changes, as revealed by RNA-seq analysis. To identify drug-related genes epigenetically silenced in the resistant strain but highly active in a sensitive strain, we compared the expression levels of the genes affected by TSA and MTZ treatment with their baseline expression profiles in both resistant and sensitive strains. This analysis identified 130 candidate genes differentially expressed in the sensitive strain NYH209, less expressed in the resistant B7268 strain, that exhibited significant expression changes upon TSA and MTZ treatment. Functional validation involved transfecting the B7268 strain with plasmids encoding four individual candidate genes: a thioredoxin reductase (TrxR), a cysteine synthase (CS), and two genes containing Myb domains (Myb5 and Myb6). Overexpression of three of these genes resulted in a marked reduction in MTZ resistance, demonstrating their role in modulating drug sensitivity. Our findings identified three novel genes that modulate drug resistance in T. vaginalis. This study reveals a previously unknown epigenetic mechanism underlying drug resistance and highlights the therapeutic potential of targeting epigenetic factors, such as HDACs, to overcome resistance and improve treatment efficacy.
Fil: Seifert Gorzycki, Julieta Lara. Universidad Nacional de San Martin. Instituto Tecnologico de Chascomus. - Consejo Nacional de Investigaciones Cientificas y Tecnicas. Centro Cientifico Tecnologico Conicet - la Plata. Instituto Tecnologico de Chascomus.; Argentina
Fil: Muñoz, Daniela. Universidad Nacional de San Martin. Instituto Tecnologico de Chascomus. - Consejo Nacional de Investigaciones Cientificas y Tecnicas. Centro Cientifico Tecnologico Conicet - la Plata. Instituto Tecnologico de Chascomus.; Argentina
Fil: Lizarraga, Ayelen. Universidad Nacional de San Martin. Instituto Tecnologico de Chascomus. - Consejo Nacional de Investigaciones Cientificas y Tecnicas. Centro Cientifico Tecnologico Conicet - la Plata. Instituto Tecnologico de Chascomus.; Argentina
Fil: Iriarte, Lucrecia Soledad. Universidad Nacional de San Martin. Instituto Tecnologico de Chascomus. - Consejo Nacional de Investigaciones Cientificas y Tecnicas. Centro Cientifico Tecnologico Conicet - la Plata. Instituto Tecnologico de Chascomus.; Argentina
Fil: Cóceres, Verónica Mabel. Universidad Nacional de San Martin. Instituto Tecnologico de Chascomus. - Consejo Nacional de Investigaciones Cientificas y Tecnicas. Centro Cientifico Tecnologico Conicet - la Plata. Instituto Tecnologico de Chascomus.; Argentina
Fil: Strobl Mazzulla, Pablo Hernán. Universidad Nacional de San Martin. Instituto Tecnologico de Chascomus. - Consejo Nacional de Investigaciones Cientificas y Tecnicas. Centro Cientifico Tecnologico Conicet - la Plata. Instituto Tecnologico de Chascomus.; Argentina
Fil: de Miguel, Natalia. Universidad Nacional de San Martin. Instituto Tecnologico de Chascomus. - Consejo Nacional de Investigaciones Cientificas y Tecnicas. Centro Cientifico Tecnologico Conicet - la Plata. Instituto Tecnologico de Chascomus.; Argentina
description Trichomoniasis, caused by the parasite Trichomonas vaginalis, is the most common non-viral sexually transmitted infection. Current treatment relies exclusively on 5-nitroimidazole drugs, with metronidazole (MTZ) as the primary option. However, the increasing prevalence of MTZ-resistant strains poses a significant challenge, particularly in the current absence of alternative therapies. Several studies have revealed that the development of metronidazole resistance in T. vaginalis is linked to genomic and transcriptional alterations. Given the role of epigenetic regulation in controlling gene expression, we investigated whether targeting histone deacetylase (HDAC) enzymes could influence drug resistance. Treatment of an MTZ-resistant strain (B7268) with the HDAC inhibitor, trichostatin A (TSA), in combination with MTZ enhanced drug sensitivity and induced significant genome-wide transcriptional changes, as revealed by RNA-seq analysis. To identify drug-related genes epigenetically silenced in the resistant strain but highly active in a sensitive strain, we compared the expression levels of the genes affected by TSA and MTZ treatment with their baseline expression profiles in both resistant and sensitive strains. This analysis identified 130 candidate genes differentially expressed in the sensitive strain NYH209, less expressed in the resistant B7268 strain, that exhibited significant expression changes upon TSA and MTZ treatment. Functional validation involved transfecting the B7268 strain with plasmids encoding four individual candidate genes: a thioredoxin reductase (TrxR), a cysteine synthase (CS), and two genes containing Myb domains (Myb5 and Myb6). Overexpression of three of these genes resulted in a marked reduction in MTZ resistance, demonstrating their role in modulating drug sensitivity. Our findings identified three novel genes that modulate drug resistance in T. vaginalis. This study reveals a previously unknown epigenetic mechanism underlying drug resistance and highlights the therapeutic potential of targeting epigenetic factors, such as HDACs, to overcome resistance and improve treatment efficacy.
publishDate 2025
dc.date.none.fl_str_mv 2025-01
dc.type.none.fl_str_mv info:eu-repo/semantics/article
info:eu-repo/semantics/publishedVersion
http://purl.org/coar/resource_type/c_6501
info:ar-repo/semantics/articulo
format article
status_str publishedVersion
dc.identifier.none.fl_str_mv http://hdl.handle.net/11336/266739
Seifert Gorzycki, Julieta Lara; Muñoz, Daniela; Lizarraga, Ayelen; Iriarte, Lucrecia Soledad; Cóceres, Verónica Mabel; et al.; Targeting histone acetylation to overcome drug resistance in the parasite Trichomonas vaginalis; Cold Spring Harbor Laboratory Press; BioRxiv; 2025; 1-2025; 1-29
2692-8205
CONICET Digital
CONICET
url http://hdl.handle.net/11336/266739
identifier_str_mv Seifert Gorzycki, Julieta Lara; Muñoz, Daniela; Lizarraga, Ayelen; Iriarte, Lucrecia Soledad; Cóceres, Verónica Mabel; et al.; Targeting histone acetylation to overcome drug resistance in the parasite Trichomonas vaginalis; Cold Spring Harbor Laboratory Press; BioRxiv; 2025; 1-2025; 1-29
2692-8205
CONICET Digital
CONICET
dc.language.none.fl_str_mv eng
language eng
dc.relation.none.fl_str_mv info:eu-repo/semantics/altIdentifier/doi/10.1101/2025.01.07.631743
info:eu-repo/semantics/altIdentifier/url/https://www.biorxiv.org/content/10.1101/2025.01.07.631743v1
dc.rights.none.fl_str_mv info:eu-repo/semantics/openAccess
https://creativecommons.org/licenses/by/2.5/ar/
eu_rights_str_mv openAccess
rights_invalid_str_mv https://creativecommons.org/licenses/by/2.5/ar/
dc.format.none.fl_str_mv application/pdf
application/pdf
dc.publisher.none.fl_str_mv Cold Spring Harbor Laboratory Press
publisher.none.fl_str_mv Cold Spring Harbor Laboratory Press
dc.source.none.fl_str_mv reponame:CONICET Digital (CONICET)
instname:Consejo Nacional de Investigaciones Científicas y Técnicas
reponame_str CONICET Digital (CONICET)
collection CONICET Digital (CONICET)
instname_str Consejo Nacional de Investigaciones Científicas y Técnicas
repository.name.fl_str_mv CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicas
repository.mail.fl_str_mv dasensio@conicet.gov.ar; lcarlino@conicet.gov.ar
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score 13.070432

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