ArticleAntimicrobial agents and chemotherapy2004
Chemosensitization of fluconazole resistance in Saccharomyces cerevisiae and pathogenic fungi by a D-octapeptide derivative.
Article in Antimicrobial agents and chemotherapy, 2004. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 55 papers.
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Who cites it
55 citing papers in PubMed, 115 citations in OpenAlex.
- Batzelladine D, a Marine Natural Product, Reverses the Fluconazole Resistance Phenotype Mediated by Transmembrane Transporters inMarine drugs · 2024Article
- Azole Combinations and Multi-Targeting Drugs That Synergistically InhibitJournal of fungi (Basel, Switzerland) · 2024Review
- Antifungal activity of β-lapachone against a fluconazole-resistant Candida auris strain.Brazilian journal of microbiology : [publication of the Brazilian Society for Microbiology] · 2024Article
- Modulators of Candida albicans Membrane Drug Transporters: A Lucrative Portfolio for the Development of Effective Antifungals.Molecular biotechnology · 2024Review
- Synthesis of Altissimacoumarin D and Other Prenylated Coumarins and Their Ability to Reverse the Multidrug Resistance Phenotype inJournal of fungi (Basel, Switzerland) · 2023Article
- Functional Expression of RecombinantJournal of fungi (Basel, Switzerland) · 2023Article
- Digoxin Derivatives Sensitize aJournal of fungi (Basel, Switzerland) · 2022Article
- Inhibitor-Resistant Mutants Give Important Insights into Candida albicans ABC Transporter Cdr1 Substrate Specificity and Help Elucidate Efflux Pump Inhibition.Antimicrobial agents and chemotherapy · 2022Article
- Article
- PDR TransporterFrontiers in microbiology · 2021Article
- β-Lapachone enhances the antifungal activity of fluconazole against a Pdr5p-mediated resistant Saccharomyces cerevisiae strain.Brazilian journal of microbiology : [publication of the Brazilian Society for Microbiology] · 2020Article
- High Efficiency Drug Repurposing Design for New Antifungal Agents.Methods and protocols · 2019Article
- FK506 Resistance ofAntimicrobial agents and chemotherapy · 2019Article
- The Candida albicans Inhibitory Activity of the Extract from Papaya (Carica papaya L.) Seed Relates to Mitochondria Dysfunction.International journal of molecular sciences · 2017Article
- Role of Ectopic Gene Conversion in the Evolution of aGenetics · 2017Article
- Review
- Synthetic Organotellurium Compounds Sensitize Drug-Resistant Candida albicans Clinical Isolates to Fluconazole.Antimicrobial agents and chemotherapy · 2017Article
- Chemosensitization ofFrontiers in plant science · 2017Article
- Targeting efflux pumps to overcome antifungal drug resistance.Future medicinal chemistry · 2016Review
- A complex game of hide and seek: the search for new antifungals.MedChemComm · 2016Article
Corrections and comments
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Authors and funding
11 authors at 4 institutions in 3 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Hyperexpression of the Saccharomyces cerevisiae multidrug ATP-binding cassette (ABC) transporter Pdr5p was driven by the pdr1-3 mutation in the Pdr1p transcriptional regulator in a strain (AD/PDR5(+)) with deletions of five other ABC-type multidrug efflux pumps. The strain had high-level fluconazole (FLC) resistance (MIC, 600 microg ml(-1)), and plasma membrane fractions showed oligomycin-sensitive ATPase activity up to fivefold higher than that shown by fractions from an isogenic PDR5-null mutant (FLC MIC, 0.94 microg ml(-1)). In vitro inhibition of the Pdr5p ATPase activity and chemosensitization of cells to FLC allowed the systematic screening of a 1.8-million-member designer D-octapeptide combinatorial library for surface-active Pdr5p antagonists with modest toxicity against yeast cells. Library deconvolution identified the 4-methoxy-2,3,6-trimethylbenzensulfonyl-substituted D-octapeptide KN20 as a potent Pdr5p ATPase inhibitor (concentration of drug causing 50% inhibition of enzyme activity [IC(50)], 4 microM) which chemosensitized AD/PDR5(+) to FLC, itraconazole, and ketoconazole. It also inhibited the ATPase activity of other ABC transporters, such as Candida albicans Cdr1p (IC(50), 30 microM) and Cdr2p (IC(50), 2 microM), and chemosensitized clinical isolates of pathogenic Candida species and S. cerevisiae strains that heterologously hyperexpressed either ABC-type multidrug efflux pumps, the C. albicans major facilitator superfamily-type drug transporter Ben(R)p, or the FLC drug target lanosterol 14 alpha-demethylase (Erg11p). Although KN20 also inhibited the S. cerevisiae plasma membrane proton pump Pma1p (IC(50), 1 microM), the peptide concentrations required for chemosensitization made yeast cells permeable to rhodamine 6G. KN20 therefore appears to indirectly chemosensitize cells to FLC by a nonlethal permeabilization of the fungal plasma membrane.
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