β-Lapachone enhances the antifungal activity of fluconazole against a Pdr5p-mediated resistant Saccharomyces cerevisiae strain
- 10 March 2020
- journal article
- research article
- Published by Springer Science and Business Media LLC in Brazilian Journal of Microbiology
- Vol. 51 (3), 1051-1060
- https://doi.org/10.1007/s42770-020-00254-9
Abstract
Objectives 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. Methods 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. Results 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. Conclusions 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.Keywords
Funding Information
- CAPES (001)
This publication has 44 references indexed in Scilit:
- The Quorum-Sensing Molecule Farnesol Is a Modulator of Drug Efflux Mediated by ABC Multidrug Transporters and Synergizes with Drugs in Candida albicansAntimicrobial Agents and Chemotherapy, 2011
- Labeling Mitochondria with JC-1Cold Spring Harbor Protocols, 2011
- Inhibitory effects of gallic acid ester derivatives onSaccharomyces cerevisiaemultidrug resistance protein Pdr5pFEMS Yeast Research, 2010
- Identification of Nile red as a fluorescent substrate of the Candida albicans ATP-binding cassette transporters Cdr1p and Cdr2p and the major facilitator superfamily transporter Mdr1pAnalytical Biochemistry, 2009
- In vitro synergic effect of ²-lapachone and isoniazid on the growth of Mycobacterium fortuitum and Mycobacterium smegmatisMemórias do Instituto Oswaldo Cruz, 2009
- Ibuprofen reverts antifungal resistance onCandida albicansshowing overexpression of CDR genesFEMS Yeast Research, 2009
- Mitochondrial disruption and DNA fragmentation in Trypanosoma cruzi induced by naphthoimidazoles synthesized from β-lapachoneZeitschrift für Parasitenkunde, 2007
- β-lapachone Activates a Mre11p-Tel1p G1/S Checkpoint in Budding YeastCell Cycle, 2006
- Molecular cloning and characterization of a novel gene of Candida albicans, CDR1, conferring multiple resistance to drugs and antifungalsCurrent Genetics, 1995
- The Constitution of Lapachol and its Derivatives. Part IV.1 Oxidation with Potassium Permanganate2,3Journal of the American Chemical Society, 1936