Affiliation:
1. Department of Clinical Pharmacy, Division of Clinical and Experimental Therapeutics, College of Pharmacy, University of Tennessee Health Sciences Center, Memphis, Tennessee, USA
Abstract
ABSTRACT
The azole antifungals arrest fungal growth through inhibition of ergosterol biosynthesis. We recently reported that a
Candida albicans
vps21
Δ/Δ mutant, deficient in membrane trafficking through the late endosome/prevacuolar compartment (PVC), continues to grow in the presence of the azoles despite the depletion of cellular ergosterol. Here, we report that the
vps21
Δ/Δ mutant exhibits less plasma membrane damage upon azole treatment than the wild type, as measured by the release of a cytoplasmic luciferase reporter into the culture supernatant. Our results also reveal that the
vps21
Δ/Δ mutant has abnormal levels of intracellular Ca
2+
and, in the presence of fluconazole, enhanced expression of a calcineurin-responsive
RTA2-GFP
reporter. Furthermore, the azole tolerance phenotype of the
vps21
Δ/Δ mutant is dependent upon both extracellular calcium levels and calcineurin activity. These findings underscore the importance of endosomal trafficking in determining the cellular consequences of azole treatment and indicate that this may occur through modulation of calcium- and calcineurin-dependent responses.
Funder
HHS | NIH | National Institute of Allergy and Infectious Diseases
Publisher
American Society for Microbiology
Subject
Infectious Diseases,Pharmacology (medical),Pharmacology
Cited by
9 articles.
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