Synthetic organotelluride compounds induce the reversal of Pdr5p mediated fluconazole resistance in Saccharomyces cerevisiae
Autor(a) principal: | |
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Data de Publicação: | 2014 |
Outros Autores: | , , , , , , , |
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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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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1814268374401679360 |