Synthetic organotelluride compounds induce the reversal of Pdr5p mediated fluconazole resistance in Saccharomyces cerevisiae

Detalhes bibliográficos
Autor(a) principal: Reis de Sa, Leandro Figueira
Data de Publicação: 2014
Outros Autores: Toledo, Fabiano Travanca, Sousa, Bruno Artur de, Goncalves, Augusto Cesar, Tessis, Ana Claudia, Wendler, Edison P., Comasseto, Joao V. [UNIFESP], Dos Santos, Alcindo A., Ferreira-Pereira, Antonio
Tipo de documento: Artigo
Idioma: eng
Título da fonte: Repositório Institucional da UNIFESP
Texto Completo: http://dx.doi.org/10.1186/s12866-014-0201-y
http://repositorio.unifesp.br/handle/11600/38000
Resumo: Background: Resistance to fluconazole, a commonly used azole antifungal, is a challenge for the treatment of fungal infections. Resistance can be mediated by overexpression of ABC transporters, which promote drug efflux that requires ATP hydrolysis. the Pdr5p ABC transporter of Saccharomyces cerevisiae is a well-known model used to study this mechanism of antifungal resistance. the present study investigated the effects of 13 synthetic compounds on Pdr5p.Results: Among the tested compounds, four contained a tellurium-butane group and shared structural similarities that were absent in the other tested compounds: a lateral hydrocarbon chain and an amide group. These four compounds were capable of inhibiting Pdr5p ATPase activity by more than 90%, they demonstrated IC50 values less than 2 M and had an uncompetitive pattern of Pdr5p ATPase activity inhibition. These organotellurides did not demonstrate cytotoxicity against human erythrocytes or S. cerevisiae mutant strains (a strain that overexpress Pdr5p and a null mutant strain) even in concentrations above 100 mu M. When tested at 100 mu M, they could reverse the fluconazole resistance expressed by both the S. cerevisiae mutant strain that overexpress Pdr5p and a clinical isolate of Candida albicans.Conclusions: We have identified four organotellurides that are promising candidates for the reversal of drug resistance mediated by drug efflux pumps. These molecules will act as scaffolds for the development of more efficient and effective efflux pump inhibitors that can be used in combination therapy with available antifungals.
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spelling Synthetic organotelluride compounds induce the reversal of Pdr5p mediated fluconazole resistance in Saccharomyces cerevisiaeOrganotelluridesPdr5pFluconazole resistanceSaccharomyces cerevisiaeBackground: Resistance to fluconazole, a commonly used azole antifungal, is a challenge for the treatment of fungal infections. Resistance can be mediated by overexpression of ABC transporters, which promote drug efflux that requires ATP hydrolysis. the Pdr5p ABC transporter of Saccharomyces cerevisiae is a well-known model used to study this mechanism of antifungal resistance. the present study investigated the effects of 13 synthetic compounds on Pdr5p.Results: Among the tested compounds, four contained a tellurium-butane group and shared structural similarities that were absent in the other tested compounds: a lateral hydrocarbon chain and an amide group. These four compounds were capable of inhibiting Pdr5p ATPase activity by more than 90%, they demonstrated IC50 values less than 2 M and had an uncompetitive pattern of Pdr5p ATPase activity inhibition. These organotellurides did not demonstrate cytotoxicity against human erythrocytes or S. cerevisiae mutant strains (a strain that overexpress Pdr5p and a null mutant strain) even in concentrations above 100 mu M. When tested at 100 mu M, they could reverse the fluconazole resistance expressed by both the S. cerevisiae mutant strain that overexpress Pdr5p and a clinical isolate of Candida albicans.Conclusions: We have identified four organotellurides that are promising candidates for the reversal of drug resistance mediated by drug efflux pumps. These molecules will act as scaffolds for the development of more efficient and effective efflux pump inhibitors that can be used in combination therapy with available antifungals.Univ Fed Rio de Janeiro, CCS, Inst Microbiol Paulo Goes, Dept Microbiol Geral,Lab Bioquim Microbiana, Rio de Janeiro, RJ, BrazilUniv São Paulo, Inst Quim, Dept Quim Fundamental, São Paulo, BrazilInst Fed Educ Ciencia & Tecnol Rio de Janeiro IFR, Rio de Janeiro, RJ, BrazilUniversidade Federal de São Paulo UNIFESP, Inst Ciencias Ambientais Quim & Farmaceut, São Paulo, BrazilUniversidade Federal de São Paulo UNIFESP, Inst Ciencias Ambientais Quim & Farmaceut, São Paulo, BrazilWeb of ScienceFundação de Amparo à Pesquisa do Estado do Rio de Janeiro (FAPERJ)Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES)University of São Paulo through the NAP-CatSinQ (Research Core in Catalysis and Chemical Synthesis)FAPERJ: E-26/111.338/2013FAPESP: 2005/59572-7FAPESP: 2008/55401-1FAPESP: 2010/17228-6FAPESP: 2011/03244-2FAPESP: 2011/11613-8FAPESP: 2012/17093-9CNPq: 470360/2012-7Biomed Central LtdUniversidade Federal do Rio de Janeiro (UFRJ)Universidade de São Paulo (USP)Inst Fed Educ Ciencia & Tecnol Rio de Janeiro IFRUniversidade Federal de São Paulo (UNIFESP)Reis de Sa, Leandro FigueiraToledo, Fabiano TravancaSousa, Bruno Artur deGoncalves, Augusto CesarTessis, Ana ClaudiaWendler, Edison P.Comasseto, Joao V. [UNIFESP]Dos Santos, Alcindo A.Ferreira-Pereira, Antonio2016-01-24T14:37:36Z2016-01-24T14:37:36Z2014-07-26info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersion9application/pdfhttp://dx.doi.org/10.1186/s12866-014-0201-yBmc Microbiology. London: Biomed Central Ltd, v. 14, 9 p., 2014.10.1186/s12866-014-0201-yWOS000339838500001.pdf1471-2180http://repositorio.unifesp.br/handle/11600/38000WOS:000339838500001engBmc Microbiologyinfo:eu-repo/semantics/openAccessreponame:Repositório Institucional da UNIFESPinstname:Universidade Federal de São Paulo (UNIFESP)instacron:UNIFESP2024-08-01T02:20:46Zoai:repositorio.unifesp.br/:11600/38000Repositório InstitucionalPUBhttp://www.repositorio.unifesp.br/oai/requestbiblioteca.csp@unifesp.bropendoar:34652024-08-01T02:20:46Repositório Institucional da UNIFESP - Universidade Federal de São Paulo (UNIFESP)false
dc.title.none.fl_str_mv Synthetic organotelluride compounds induce the reversal of Pdr5p mediated fluconazole resistance in Saccharomyces cerevisiae
title Synthetic organotelluride compounds induce the reversal of Pdr5p mediated fluconazole resistance in Saccharomyces cerevisiae
spellingShingle Synthetic organotelluride compounds induce the reversal of Pdr5p mediated fluconazole resistance in Saccharomyces cerevisiae
Reis de Sa, Leandro Figueira
Organotellurides
Pdr5p
Fluconazole resistance
Saccharomyces cerevisiae
title_short Synthetic organotelluride compounds induce the reversal of Pdr5p mediated fluconazole resistance in Saccharomyces cerevisiae
title_full Synthetic organotelluride compounds induce the reversal of Pdr5p mediated fluconazole resistance in Saccharomyces cerevisiae
title_fullStr Synthetic organotelluride compounds induce the reversal of Pdr5p mediated fluconazole resistance in Saccharomyces cerevisiae
title_full_unstemmed Synthetic organotelluride compounds induce the reversal of Pdr5p mediated fluconazole resistance in Saccharomyces cerevisiae
title_sort Synthetic organotelluride compounds induce the reversal of Pdr5p mediated fluconazole resistance in Saccharomyces cerevisiae
author Reis de Sa, Leandro Figueira
author_facet Reis de Sa, Leandro Figueira
Toledo, Fabiano Travanca
Sousa, Bruno Artur de
Goncalves, Augusto Cesar
Tessis, Ana Claudia
Wendler, Edison P.
Comasseto, Joao V. [UNIFESP]
Dos Santos, Alcindo A.
Ferreira-Pereira, Antonio
author_role author
author2 Toledo, Fabiano Travanca
Sousa, Bruno Artur de
Goncalves, Augusto Cesar
Tessis, Ana Claudia
Wendler, Edison P.
Comasseto, Joao V. [UNIFESP]
Dos Santos, Alcindo A.
Ferreira-Pereira, Antonio
author2_role author
author
author
author
author
author
author
author
dc.contributor.none.fl_str_mv Universidade Federal do Rio de Janeiro (UFRJ)
Universidade de São Paulo (USP)
Inst Fed Educ Ciencia & Tecnol Rio de Janeiro IFR
Universidade Federal de São Paulo (UNIFESP)
dc.contributor.author.fl_str_mv Reis de Sa, Leandro Figueira
Toledo, Fabiano Travanca
Sousa, Bruno Artur de
Goncalves, Augusto Cesar
Tessis, Ana Claudia
Wendler, Edison P.
Comasseto, Joao V. [UNIFESP]
Dos Santos, Alcindo A.
Ferreira-Pereira, Antonio
dc.subject.por.fl_str_mv Organotellurides
Pdr5p
Fluconazole resistance
Saccharomyces cerevisiae
topic Organotellurides
Pdr5p
Fluconazole resistance
Saccharomyces cerevisiae
description Background: Resistance to fluconazole, a commonly used azole antifungal, is a challenge for the treatment of fungal infections. Resistance can be mediated by overexpression of ABC transporters, which promote drug efflux that requires ATP hydrolysis. the Pdr5p ABC transporter of Saccharomyces cerevisiae is a well-known model used to study this mechanism of antifungal resistance. the present study investigated the effects of 13 synthetic compounds on Pdr5p.Results: Among the tested compounds, four contained a tellurium-butane group and shared structural similarities that were absent in the other tested compounds: a lateral hydrocarbon chain and an amide group. These four compounds were capable of inhibiting Pdr5p ATPase activity by more than 90%, they demonstrated IC50 values less than 2 M and had an uncompetitive pattern of Pdr5p ATPase activity inhibition. These organotellurides did not demonstrate cytotoxicity against human erythrocytes or S. cerevisiae mutant strains (a strain that overexpress Pdr5p and a null mutant strain) even in concentrations above 100 mu M. When tested at 100 mu M, they could reverse the fluconazole resistance expressed by both the S. cerevisiae mutant strain that overexpress Pdr5p and a clinical isolate of Candida albicans.Conclusions: We have identified four organotellurides that are promising candidates for the reversal of drug resistance mediated by drug efflux pumps. These molecules will act as scaffolds for the development of more efficient and effective efflux pump inhibitors that can be used in combination therapy with available antifungals.
publishDate 2014
dc.date.none.fl_str_mv 2014-07-26
2016-01-24T14:37:36Z
2016-01-24T14:37:36Z
dc.type.driver.fl_str_mv info:eu-repo/semantics/article
dc.type.status.fl_str_mv info:eu-repo/semantics/publishedVersion
format article
status_str publishedVersion
dc.identifier.uri.fl_str_mv http://dx.doi.org/10.1186/s12866-014-0201-y
Bmc Microbiology. London: Biomed Central Ltd, v. 14, 9 p., 2014.
10.1186/s12866-014-0201-y
WOS000339838500001.pdf
1471-2180
http://repositorio.unifesp.br/handle/11600/38000
WOS:000339838500001
url http://dx.doi.org/10.1186/s12866-014-0201-y
http://repositorio.unifesp.br/handle/11600/38000
identifier_str_mv Bmc Microbiology. London: Biomed Central Ltd, v. 14, 9 p., 2014.
10.1186/s12866-014-0201-y
WOS000339838500001.pdf
1471-2180
WOS:000339838500001
dc.language.iso.fl_str_mv eng
language eng
dc.relation.none.fl_str_mv Bmc Microbiology
dc.rights.driver.fl_str_mv info:eu-repo/semantics/openAccess
eu_rights_str_mv openAccess
dc.format.none.fl_str_mv 9
application/pdf
dc.publisher.none.fl_str_mv Biomed Central Ltd
publisher.none.fl_str_mv Biomed Central Ltd
dc.source.none.fl_str_mv reponame:Repositório Institucional da UNIFESP
instname:Universidade Federal de São Paulo (UNIFESP)
instacron:UNIFESP
instname_str Universidade Federal de São Paulo (UNIFESP)
instacron_str UNIFESP
institution UNIFESP
reponame_str Repositório Institucional da UNIFESP
collection Repositório Institucional da UNIFESP
repository.name.fl_str_mv Repositório Institucional da UNIFESP - Universidade Federal de São Paulo (UNIFESP)
repository.mail.fl_str_mv biblioteca.csp@unifesp.br
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