Trafficking through the Late Endosome Significantly Impacts Candida albicans Tolerance of the Azole Antifungals
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The azole antifungals block ergosterol biosynthesis by inhibiting lanosterol demethylase (Erg11p). The resulting depletion of cellular ergosterol and the accumulation of “toxic” sterol intermediates are both thought to compromise plasma membrane function. However, the effects of ergosterol depletion upon the function of intracellular membranes and organelles are not well described. The purpose of this study was to characterize the effects of azole treatment upon the integrity of the Candida albicans vacuole and to determine whether, in turn, vacuolar trafficking influences azole susceptibility. Profound fragmentation of the C. albicans vacuole can be observed as an early consequence of azole treatment, and it precedes significant growth inhibition. In addition, a C. albicans vps21 Δ/Δ mutant, blocked in membrane trafficking through the late endosomal prevacuolar compartment (PVC), is able to grow significantly more than the wild type in the presence of several azole antifungals under standard susceptibility testing conditions. Furthermore, the vps21 Δ/Δ mutant is able to grow despite the depletion of cellular ergosterol. This phenotype resembles an exaggerated form of “trailing growth” that has been described for some clinical isolates. In contrast, the vps21 Δ/Δ mutant is hypersensitive to drugs that block alternate steps in ergosterol biosynthesis. On the basis of these results, we propose that endosomal trafficking defects may lead to the cellular “redistribution” of the sterol intermediates that accumulate following inhibition of ergosterol biosynthesis. Furthermore, the destination of these intermediates, or the precise cellular compartments in which they accumulate, may be an important determinant of their toxicity and thus ultimately antifungal efficacy.
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MIC measurements have been optimized to minimize or ignore residual fungal growth, termed tolerance or trailing growth, which is detected in 25-60% of clinical isolates.
“MIC measurements have been optimized to minimize or ignore residual fungal growth 4,18 , termed”
From Antifungal tolerance is a subpopulation effect distinct from resistance and is associated with persistent candidemia (2018) · cites this paper as [19]
The Results (p. 6) explain that a 50% growth-inhibition MIC cutoff, rather than an 80% cutoff, changes how trailing growth is classified. This supports the idea that an MIC measurement can tolerate residual growth, but the paper does not say MIC measurements generally have been optimized to minimize or ignore it. The citation appears beside that measurement claim, not the later prevalence figure. (LLM, conf=0.79)
Experimental — accuracy not yet measuredTolerance can be affected by several adjuvant drugs, iron levels, genes involved in vacuolar protein sorting, and calcium flux.
“Tolerance can be affected by several adjuvant drugs 12 , iron levels 26 , and genes involved in vacuolar protein sorting 19 , as well as calcium flux 14,27,28 .”
From Antifungal tolerance is a subpopulation effect distinct from resistance and is associated with persistent candidemia (2018) · cites this paper as [19]
Tolerance is related to phenomena previously described as trailing growth, tolerance, or Hsp90-dependent resistance.
“Tolerance is related to phenomena previously described as “trailing growth” 19,[22][23][24]32,33,59 , “tolerance” 5,26,60 , or Hsp90dependent “resistance” 10,28,44,61 .”
From Antifungal tolerance is a subpopulation effect distinct from resistance and is associated with persistent candidemia (2018) · cites this paper as [19]
IRO1 and VPS21 affected FoG and not RAD.
“In addition, IRO1 (Supplementary Note 2), which is involved in iron homeostasis 26 , and VPS21, which is involved in vacuolar trafficking 19 , affected FoG and not RAD.”
From Antifungal tolerance is a subpopulation effect distinct from resistance and is associated with persistent candidemia (2018) · cites this paper as [19]
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Luna-Tapia, A., Peters, B. M., Eberle, K. E., Kerns, M. E., Foster, T. P., Marrero, L., Noverr, M. C., Fidel, P. L., & Palmer, G. E. (2015) · Eukaryotic Cell · doi:10.1128/ec.00116-15 · Cited by 35 · see citing works
Self-citationIdentification and characterization of mediators of fluconazole tolerance in Candida albicans
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Self-citationEndosomal Trafficking Defects Can Induce Calcium-Dependent Azole Tolerance in Candida albicans
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Self-citationPeters, B. M., Luna-Tapia, A., Tournu, H., Rybak, J. M., Rogers, P. D., & Palmer, G. E. (2017) · Antimicrobial Agents and Chemotherapy · doi:10.1128/aac.00084-17 · Cited by 12 · see citing works
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- Authors
- Luna-Tapia, A., Kerns, M. E., Eberle, K. E., Jursic, B. S., & Palmer, G. E.
- Affiliations
- Louisiana State University (US)
- LSU New Orleans (US)
- ORCID
- Palmer, Glen E.
- Venue
- Antimicrobial Agents and Chemotherapy
- Publisher
- American Society for Microbiology
- Published
- 2015-04
- Volume
- 59
- Issue
- 4
- Pages
- 2410-2420
- ISSN
- 0066-4804 (ISSN-L)
- 1098-6596
- PMC
- PMC4356793
- OpenAlex
- W2009729619
- Cited by
- 28
- References
- 55
- Citations by year
- 2026: 3 · 2025: 1 · 2024: 1 · 2023: 1 · 2022: 2 · 2021: 1 · 2020: 2 · 2019: 6 · 2018: 3 · 2017: 3 · 2016: 2 · 2015: 3
- FWCI
- 2.85
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Antimicrobial Agents and Chemotherapy (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Repositorio Institucional Universidad de Sucre (submittedVersion, cc-by-nc-nd)
- Funders
- University of Missouri
- University of Minnesota
- Carnegie Mellon University
- Georgetown University
- University of Missouri-Kansas City
- National Institutes of Health
- National Institute of Allergy and Infectious Diseases (R21AI097664, R01AI099080)
- Topics
- Health Sciences › Medicine › Infectious Diseases › Antifungal resistance and susceptibility
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Fungal and yeast genetics research
- Health Sciences › Medicine › Epidemiology › Fungal Infections and Studies
- Keywords
- Candida albicans, azole antifungals, drug resistance, late endosomes, vacuole fragmentation, prevacuolar compartment, membrane trafficking, ergosterol biosynthesis, sterol intermediates, antifungal susceptibility
- MeSH terms
- Antifungal Agents, Azoles, Candida albicans, Ergosterol, Microbial Sensitivity Tests, Plasmids, Endosomes, Vacuoles, Drug Resistance, Fungal
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