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Published on: December 28, 2017
Unusual susceptibility of a multidrug-resistant yeast strain to peptidic antifungals
S Milewski1, F Mignini, R Prasad
1Department of Pharmaceutical Technology and Biochemistry, Technical University of Gdańsk, Gdańsk, Poland. milewski@altis.chem.pg.gda.pl
Abstract:
The susceptibility of Saccharomyces cerevisiae JG436 multidrug transporter deletion mutant, Deltapdr5, to several antifungal agents was compared to that of JG436-derived JGCDR1 and JGCaMDR1 transformants, harboring the CDR1 and CaMDR1 genes, encoding the main drug-extruding membrane proteins of Candida albicans. The JGCDR1 and JGCaMDR1 yeasts demonstrated markedly diminished susceptibility to the azole antifungals, terbinafine and cycloheximide, while that to amphotericin B was unchanged. Surprisingly, JGCDR1 but not JGCaMDR1 cells showed enhanced susceptibility to peptidic antifungals, rationally designed compounds containing inhibitors of glucosamine-6-phosphate synthase. It was found that these antifungal oligopeptides, as well as model oligopeptides built of proteinogenic amino acids, were not effluxed from JGCDR1 cells. Moreover, they were taken up by these cells at rates two to three times higher than by JG436. The tested oligopeptides were rapidly cleaved to constitutive amino acids by cytoplasmic peptidases. Studies on the mechanism of the observed phenomenon suggested that an additive proton motive force generated by Cdr1p stimulated uptake of oligopeptides into JGCDR1 cells, thus giving rise to the higher antifungal activity of FMDP [N(3)-(4-methoxyfumaroyl)-L-2,3-diaminopropanoic acid]-peptides.
Insights
Candida albicans drug transporters Cdr1p and CaMdr1p influence antifungal susceptibility. Cdr1p enhances uptake of specific peptidic antifungals, increasing their efficacy.
Area of Science:
- Microbiology
- Molecular Biology
- Biochemistry
Background:
- Multidrug transporters like Pdr5p in Saccharomyces cerevisiae and Cdr1p/CaMdr1p in Candida albicans play a crucial role in antifungal resistance.
- Understanding the substrate specificity and transport mechanisms of these efflux pumps is vital for developing new antifungal strategies.
Purpose of the Study:
- To investigate the impact of Candida albicans multidrug transporters Cdr1p and CaMdr1p on the susceptibility of Saccharomyces cerevisiae to various antifungal agents.
- To elucidate the mechanism by which these transporters affect the uptake and efficacy of novel peptidic antifungals.
Main Methods:
- Comparative susceptibility testing of Saccharomyces cerevisiae deletion mutant (Deltapdr5) and transformants expressing Cdr1p (JGCDR1) or CaMdr1p (JGCaMDR1) against azoles, terbinafine, cycloheximide, amphotericin B, and peptidic antifungals.
- Analysis of oligopeptide efflux and uptake rates in different yeast strains.
- Investigation of the role of proton motive force and cytoplasmic peptidases in oligopeptide transport and metabolism.
Main Results:
- JGCDR1 and JGCaMDR1 transformants showed reduced susceptibility to azoles, terbinafine, and cycloheximide, but not amphotericin B.
- Surprisingly, JGCDR1 cells exhibited increased susceptibility to peptidic antifungals, with enhanced uptake and no efflux observed.
- Oligopeptides were rapidly cleaved by cytoplasmic peptidases, and Cdr1p-generated proton motive force appeared to stimulate oligopeptide uptake in JGCDR1 cells.
Conclusions:
- Candida albicans Cdr1p and CaMdr1p significantly modulate yeast susceptibility to conventional antifungals.
- Cdr1p actively facilitates the uptake of specific peptidic antifungals, leading to increased intracellular accumulation and enhanced antifungal activity.
- The findings suggest a potential therapeutic strategy involving Cdr1p-mediated uptake of peptidic antifungals for overcoming drug resistance.
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