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β-Lapachone enhances the antifungal activity of fluconazole against a Pdr5p-mediated resistant Saccharomyces cerevisiae strain.

Authors
  • de Moraes, Daniel Clemente1
  • Cardoso, Karina Martins2
  • Domingos, Levy Tenório Sousa1
  • do Carmo Freire Ribeiro Pinto, Maria3
  • Monteiro, Robson Q2
  • Ferreira-Pereira, Antônio4
  • 1 Laboratório de Bioquímica Microbiana, Instituto de Microbiologia Paulo de Góes, Centro de Ciências da Saúde, Universidade Federal do Rio de Janeiro, Avenida Carlos Chagas Filho 373, Cidade Universitária, Rio de Janeiro, RJ, CEP: 21941-590, Brazil. , (Brazil)
  • 2 Instituto de Bioquímica Médica Leopoldo de Meis, Centro de Ciências da Saúde, Universidade Federal do Rio de Janeiro, Avenida Carlos Chagas Filho 373, Cidade Universitária, Rio de Janeiro, RJ, CEP: 21941-590, Brazil. , (Brazil)
  • 3 Laboratório de Química Heterocíclica, Instituto de Pesquisas de Produtos Naturais, Centro de Ciências da Saúde, Universidade Federal do Rio de Janeiro, Avenida Carlos Chagas Filho 373, Cidade Universitária, Rio de Janeiro, RJ, CEP: 21941-590, Brazil. , (Brazil)
  • 4 Laboratório de Bioquímica Microbiana, Instituto de Microbiologia Paulo de Góes, Centro de Ciências da Saúde, Universidade Federal do Rio de Janeiro, Avenida Carlos Chagas Filho 373, Cidade Universitária, Rio de Janeiro, RJ, CEP: 21941-590, Brazil. [email protected] , (Brazil)
Type
Published Article
Journal
Brazilian journal of microbiology : [publication of the Brazilian Society for Microbiology]
Publication Date
Sep 01, 2020
Volume
51
Issue
3
Pages
1051–1060
Identifiers
DOI: 10.1007/s42770-020-00254-9
PMID: 32157667
Source
Medline
Keywords
Language
English
License
Unknown

Abstract

The aim of this study was to evaluate the ability of lapachones in disrupting the fungal multidrug resistance (MDR) phenotype, using a model of study which an azole-resistant Saccharomyces cerevisiae mutant strain that overexpresses the ATP-binding cassette (ABC) transporter Pdr5p. The evaluation of the antifungal activity of lapachones and their possible synergism with fluconazole against the mutant S. cerevisiae strain was performed through broth microdilution and spot assays. Reactive oxygen species (ROS) and efflux pump activity were assessed by fluorometry. ATPase activity was evaluated by the Fiske and Subbarow method. The effect of β-lapachone on PDR5 mRNA expression was assessed by RT-PCR. The release of hemoglobin was measured to evaluate the hemolytic activity of β-lapachone. α-nor-Lapachone and β-lapachone inhibited S. cerevisiae growth at 100 μg/ml. Only β-lapachone enhanced the antifungal activity of fluconazole, and this combined action was inhibited by ascorbic acid. β-Lapachone induced the production of ROS, inhibited Pdr5p-mediated efflux, and impaired Pdr5p ATPase activity. Also, β-lapachone neither affected the expression of PDR5 nor exerted hemolytic activity. Data obtained indicate that β-lapachone is able to inhibit the S. cerevisiae efflux pump Pdr5p. Since this transporter is homologous to fungal ABC transporters, further studies employing clinical isolates that overexpress these proteins will be conducted to evaluate the effect of β-lapachone on pathogenic fungi.

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