Azole Drugs Are Imported By Facilitated Diffusion in Candida albicans and Other Pathogenic Fungi
Open accessAbstract
Despite the wealth of knowledge regarding the mechanisms of action and the mechanisms of resistance to azole antifungals, very little is known about how the azoles are imported into pathogenic fungal cells. Here the in-vitro accumulation and import of Fluconazole (FLC) was examined in the pathogenic fungus, Candida albicans. In energized cells, FLC accumulation correlates inversely with expression of ATP-dependent efflux pumps. In de-energized cells, all strains accumulate FLC, suggesting that FLC import is not ATP-dependent. The kinetics of import in de-energized cells displays saturation kinetics with a K(m) of 0.64 μM and V(max) of 0.0056 pmol/min/10⁸ cells, demonstrating that FLC import proceeds via facilitated diffusion through a transporter rather than passive diffusion. Other azoles inhibit FLC import on a mole/mole basis, suggesting that all azoles utilize the same facilitated diffusion mechanism. An analysis of related compounds indicates that competition for azole import depends on an aromatic ring and an imidazole or triazole ring together in one molecule. Import of FLC by facilitated diffusion is observed in other fungi, including Cryptococcus neoformans, Saccharomyces cerevisiae, and Candida krusei, indicating that the mechanism of transport is conserved among fungal species. FLC import was shown to vary among Candida albicans resistant clinical isolates, suggesting that altered facilitated diffusion may be a previously uncharacterized mechanism of resistance to azole drugs.
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Clinical isolates of Candida with reduced fluconazole sensitivity may exhibit altered fluconazole uptake.
“it is has been suggested that clinical isolates of Candida with reduced fluconazole sensitivity may exhibit altered fluconazole uptake (24)”
From Mutations in <i>TAC1B</i> : a Novel Genetic Determinant of Clinical Fluconazole Resistance in Candida auris (2020) · cites this paper as [24]
Maximal accumulation of fluconazole did not progress in a temperature-dependent manner, inconsistent with simple passive diffusion.
“maximal accumulation of fluconazole did not progress in a temperature-dependent manner, inconsistent with simple passive diffusion.”
From Molecular and genetic basis of azole antifungal resistance in the opportunistic pathogenic fungus<i>Candida albicans</i> (2020) · cites this paper as [160]
This mechanism of fluconazole import is likely conserved across many fungal species.
“this mechanism is likely conserved across many fungal species.”
From Molecular and genetic basis of azole antifungal resistance in the opportunistic pathogenic fungus<i>Candida albicans</i> (2020) · cites this paper as [160]
Fluconazole import displays saturation kinetics in de-energized Candida cells unable to efflux drug via active transport mechanisms like the ABC transporter Cdr1.
“fluconazole import displayed saturation kinetics in de-energized cells unable to efflux drug via active transport mechanisms like the ABC transporter Cdr1.”
From Molecular and genetic basis of azole antifungal resistance in the opportunistic pathogenic fungus<i>Candida albicans</i> (2020) · cites this paper as [160]
The altered cellular sterol composition of CG156 may affect intracellular signalling and trafficking pathways, the efflux machinery, and transport proteins proposed to mediate azole import via facilitated diffusion.
“The authors also indicate that the altered cellular sterol composition of CG156 may affect intracellular signalling and trafficking pathways, as the efflux machinery [199,211,212] and any transport proteins that are proposed to mediate azole import via facilitated diffusion [213].”
From Candida glabrata Biofilms: How Far Have We Come? (2017) · cites this paper as [213]
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Cites
Isogenic strain construction and gene mapping in Candida albicans.
Fonzi, W. A., & Irwin, M. Y. (1993) · Genetics · doi:10.1093/genetics/134.3.717 · Cited by 1,695 · see citing works
The ESCRT machinery in endosomal sorting of ubiquitylated membrane proteins
Raiborg, C., & Stenmark, H. (2009) · Nature · doi:10.1038/nature07961 · Cited by 1,408 · see citing works
Clinical, Cellular, and Molecular Factors That Contribute to Antifungal Drug Resistance
White, T. C., Marr, K. A., & Bowden, R. A. (1998) · Clinical Microbiology Reviews · doi:10.1128/cmr.11.2.382 · Cited by 1,353 · see citing works
Self-citationSanglard, D., Kuchler, K., Ischer, F., Pagani, J. L., Monod, M., & Bille, J. (1995) · Antimicrobial Agents and Chemotherapy · doi:10.1128/aac.39.11.2378 · Cited by 815 · see citing works
White, T. C. (1997) · Antimicrobial Agents and Chemotherapy · doi:10.1128/aac.41.7.1482 · Cited by 612 · see citing works
Self-citationResistance Mechanisms in Clinical Isolates of <i>Candida albicans</i>
White, T. C., Holleman, S., Dy, F., Mirels, L. F., & Stevens, D. A. (2002) · Antimicrobial Agents and Chemotherapy · doi:10.1128/aac.46.6.1704-1713.2002 · Cited by 461 · see citing works
Self-citationThe Size of the Nucleus Increases as Yeast Cells Grow
Jorgensen, P., Edgington, N. P., Schneider, B. L., Rupeš, I., Tyers, M., & Futcher, B. (2007) · Molecular Biology of the Cell · doi:10.1091/mbc.e06-10-0973 · Cited by 415 · see citing works
Putative Role of β-1,3 Glucans in <i>Candida albicans</i> Biofilm Resistance
Nett, J., Lincoln, L., Marchillo, K., Massey, R., Holoyda, K., Hoff, B., VanHandel, M., & Andes, D. (2007) · Antimicrobial Agents and Chemotherapy · doi:10.1128/aac.01056-06 · Cited by 407 · see citing works
Candidaemia in Europe: epidemiology and resistance
Tortorano, A. M., Kibbler, C. C., Pemán, J., Bernhardt, H., Klingspor, L., & Grillot, R. (2006) · International Journal of Antimicrobial Agents · doi:10.1016/j.ijantimicag.2006.01.002 · Cited by 349 · see citing works
Rewiring of the Yeast Transcriptional Network Through the Evolution of Motif Usage
Ihmels, J., Bergmann, S., Gerami‐Nejad, M., Yanai, I., McClellan, M., Berman, J. G., & Barkai, N. (2005) · Science · doi:10.1126/science.1113833 · Cited by 295 · see citing works
Multiple efflux mechanisms are involved in Candida albicans fluconazole resistance
Albertson, G. D., Niimi, M., Cannon, R. D., & Jenkinson, H. F. (1996) · Antimicrobial Agents and Chemotherapy · doi:10.1128/aac.40.12.2835 · Cited by 260 · see citing works
The genetic basis of fluconazole resistance development in Candida albicans
Morschhäuser, J. (2002) · Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease · doi:10.1016/s0925-4439(02)00087-x · Cited by 236 · see citing works
The evolution of combinatorial gene regulation in fungi
Tuch, B. B., Galgoczy, D. J., Hernday, A. D., Li, H., & Johnson, A. D. (2008) · PLoS Biology · doi:10.1371/journal.pbio.0060038 · Cited by 228 · see citing works
Recent trends in the epidemiology of invasive mycoses
Clark, T. A., & Hajjeh, R. A. (2002) · Current Opinion in Infectious Diseases · doi:10.1097/00001432-200212000-00003 · Cited by 210 · see citing works
Drug Susceptibilities of Yeast Cells Are Affected by Membrane Lipid Composition
Mukhopadhyay, K., Kohli, A., & Prasad, R. (2002) · Antimicrobial Agents and Chemotherapy · doi:10.1128/aac.46.12.3695-3705.2002 · Cited by 202 · see citing works
Lamping, E., Monk, B. C., Niimi, K., Holmes, A. R., Tsao, S., Tanabe, K., Niimi, M., Uehara, Y., & Cannon, R. D. (2007) · Eukaryotic Cell · doi:10.1128/ec.00091-07 · Cited by 192 · see citing works
Transcriptional Rewiring of Fungal Galactose-Metabolism Circuitry
Martchenko, M., Levitin, A., Hogues, H., Nantel, A., & Whiteway, M. S. (2007) · Current Biology · doi:10.1016/j.cub.2007.05.017 · Cited by 172 · see citing works
Current challenges in the management of invasive fungal infections
Lai, C., Tan, C., Huang, Y., Shao, P., & Hsueh, P. (2008) · Journal of Infection and Chemotherapy · doi:10.1007/s10156-007-0595-7 · Cited by 165 · see citing works
Rhodamine 6G efflux for the detection of CDR1-overexpressing azole-resistant Candidaalbicans strains
Maesaki, S., Marichal, P., Bossche, H. V., Sanglard, D., & Kohno, S. (1999) · Journal of Antimicrobial Chemotherapy · doi:10.1093/jac/44.1.27 · Cited by 162 · see citing works
Rational Modification of a Candidate Cancer Drug for Use Against Chagas Disease
Kraus, J. M., Verlinde, C. L. M. J., Karimi, M., et al. (2009) · Journal of Medicinal Chemistry · doi:10.1021/jm801313t · Cited by 151 · see citing works
Prasad, T., Chandra, A., Mukhopadhyay, C. K., & Prasad, R. (2006) · Antimicrobial Agents and Chemotherapy · doi:10.1128/aac.00653-06 · Cited by 149 · see citing works
White, T., Pfaller, M., Rinaldi, M., Smith, J., & Redding, S. (1997) · Oral Diseases · doi:10.1111/j.1601-0825.1997.tb00336.x · Cited by 107 · see citing works
Self-citationA concentric circle model of multivesicular body cargo sorting
Nickerson, D. P., Russell, M. R. G., & Odorizzi, G. (2007) · EMBO Reports · doi:10.1038/sj.embor.7401004 · Cited by 91 · see citing works
Papon, N., Noël, T., Florent, M., Gibot‐Leclerc, S., Jean, D., Chastin, C., Villard, J.-F., & Chapeland‐Leclerc, F. (2006) · Antimicrobial Agents and Chemotherapy · doi:10.1128/aac.00824-06 · Cited by 86 · see citing works
Development of Positive Selectable Markers for the Fungal Pathogen Cryptococcus neoformans
Hua, J., Meyer, J. D., & Lodge, J. K. (2000) · Clinical and Diagnostic Laboratory Immunology · doi:10.1128/cdli.7.1.125-128.2000 · Cited by 83 · see citing works
Transcriptional Analyses of Antifungal Drug Resistance in Candida albicans
Lyons, C. N., & White, T. C. (2000) · Antimicrobial Agents and Chemotherapy · doi:10.1128/aac.44.9.2296-2303.2000 · Cited by 79 · see citing works
Self-citationIsolation and characterization of the Saccharomyces cerevisiae SUT1 gene involved in sterol uptake
Bourot, S., & Karst, F. (1995) · Gene · doi:10.1016/0378-1119(95)00478-o · Cited by 76 · see citing works
Song, J. L., Harry, J. B., Eastman, R. T., Oliver, B. G. G., & White, T. C. (2004) · Antimicrobial Agents and Chemotherapy · doi:10.1128/aac.48.4.1136-1144.2004 · Cited by 68 · see citing works
Self-citationTetracycline alters drug susceptibility in Candida albicans and other pathogenic fungi
Oliver, B. G. G., Silver, P. M., Marie, C. S., Hoot, S. J., Leyde, S. E., & White, T. C. (2008) · Microbiology · doi:10.1099/mic.0.2007/013805-0 · Cited by 62 · see citing works
Self-citationPaclobutrazol Inhibits Abscisic Acid Biosynthesis in Cercospora rosicola
Norman, S. M., Bennett, R. D., Poling, S. M., et al. (1986) · PLANT PHYSIOLOGY · doi:10.1104/pp.80.1.122 · Cited by 54 · see citing works
Pasrija, R., Krishnamurthy, S., Prasad, T., Ernst, J. F., & Prasad, R. (2005) · Journal of Antimicrobial Chemotherapy · doi:10.1093/jac/dki112 · Cited by 53 · see citing works
Chapeland-Leclerc, F., Bouchoux, J., Goumar, A., Chastin, C., Villard, J., & Noël, T. (2005) · Antimicrobial Agents and Chemotherapy · doi:10.1128/aac.49.8.3101-3108.2005 · Cited by 48 · see citing works
Cytoplasmic localization of sterol transcription factors Upc2p and Ecm22p in S. cerevisiae
Marie, C., Leyde, S., & White, T. C. (2008) · Fungal Genetics and Biology · doi:10.1016/j.fgb.2008.07.004 · Cited by 47 · see citing works
Self-citationFungicidal activity of β‐thujaplicin analogues
Baya, M., Soulounganga, P., Gelhaye, É., et al. (2001) · Pest Management Science · doi:10.1002/ps.379 · Cited by 44 · see citing works
Eshel, D., Ben-Arie, R., Dinoor, A., et al. (2000) · Phytopathology · doi:10.1094/phyto.2000.90.11.1256 · Cited by 44 · see citing works
Candidemia in the critically ill patient
Picazo, J. J., González‐Romo, F., & Candel, F. J. (2008) · International Journal of Antimicrobial Agents · doi:10.1016/s0924-8579(08)70005-0 · Cited by 42 · see citing works
Müller, F. C., Staudigel, A., Salvenmoser, S., Tredup, A., Miltenberger, R., & Herrmann, J. V. (2007) · Antimicrobial Agents and Chemotherapy · doi:10.1128/aac.00459-07 · Cited by 40 · see citing works
Suryadevara, P. K., Olepu, S., Lockman, J. W., et al. (2009) · Journal of Medicinal Chemistry · doi:10.1021/jm900030h · Cited by 38 · see citing works
Noël, T., François, F., Paumard, P., Chastin, C., Brèthes, D., & Villard, J.-F. (2003) · Antimicrobial Agents and Chemotherapy · doi:10.1128/aac.47.4.1275-1284.2003 · Cited by 34 · see citing works
Entry of ketoconazole into Candida albicans
Boiron, P., Drouhet, E., Dupont, B., et al. (1987) · Antimicrobial Agents and Chemotherapy · doi:10.1128/aac.31.2.244 · Cited by 25 · see citing works
Transcriptional Rewiring: The Proof Is in the Eating
Rokas, A., & Hittinger, C. T. (2007) · Current Biology · doi:10.1016/j.cub.2007.06.025 · Cited by 23 · see citing works
Lamb, D. C., Kelly, D. E., Manning, N. J., et al. (2006) · FEMS Microbiology Letters · doi:10.1111/j.1574-6968.1997.tb10240.x · Cited by 21 · see citing works
Niimi, M., Wada, S.-I., Tanabe, K., Kaneko, A., Takano, Y., Umeyama, T., Hanaoka, N., Uehara, Y., Lamping, E., Niimi, K., et al. (2005) · Japanese Journal of Infectious Diseases · doi:10.7883/yoken.jjid.2005.1 · Cited by 21 · see citing works
In vivo and in vitro effects of azaconazole on renal function in the Fischer 344 rat
Rankin, G. O., Yang, D. J., Cressey‐Veneziano, K., et al. (1985) · Toxicology · doi:10.1016/0300-483x(85)90074-5 · Cited by 8 · see citing works
Flagged first, then by citations
Research works printed but not linked: 2
- [8]Sanglard D White TC 2005 Chapter 14 - Molecular Principles of Antifungal Drug Resistance. Heitman J Filler SG Edwards JE Mitchell AP Molecular principles of fungal pathogenesis Washington, D.C. ASM Press 197 212
- [22]National Center for Biotechnology Information N, NIH 2010 PubChem Compound. 2010. http://pubchem.ncbi.nlm.nih.gov/
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Azole Antifungal Resistance in Candida albicans and Emerging Non-albicans Candida Species
Whaley, S. G., Berkow, E. L., Rybak, J. M., Nishimoto, A. T., Barker, K. S., & Rogers, P. D. (2017) · Frontiers in Microbiology · doi:10.3389/fmicb.2016.02173 · Cited by 900 · see citing works
Mechanisms of Antifungal Drug Resistance
Cowen, L. E., Sanglard, D., Howard, S. J., Rogers, P. D., & Perlin, D. S. (2015) · Cold Spring Harbor Perspectives in Medicine · doi:10.1101/cshperspect.a019752 · Cited by 647 · see citing works
Regulatory circuitry governing fungal development, drug resistance, and disease.
Shapiro, R. S., Robbins, N., & Cowen, L. E. (2011) · Microbiology and Molecular Biology Reviews · doi:10.1128/mmbr.00045-10 · Cited by 576 · see citing works
Fluconazole resistance in <em>Candida</em> species: a current perspective
Berkow, E., & Lockhart, S. (2017) · Infection and Drug Resistance · doi:10.2147/idr.s118892 · Cited by 542 · see citing works
Molecular Evolution of Antifungal Drug Resistance
Robbins, N., Caplan, T., & Cowen, L. E. (2017) · Annual Review of Microbiology · doi:10.1146/annurev-micro-030117-020345 · Cited by 441 · see citing works
A Candida Biofilm-Induced Pathway for Matrix Glucan Delivery: Implications for Drug Resistance
Taff, H. T., Nett, J. E., Zarnowski, R., Ross, K. M., Sanchez, H., Cain, M. T., Hamaker, J., Mitchell, A. P., & Andes, D. R. (2012) · PLoS Pathogens · doi:10.1371/journal.ppat.1002848 · Cited by 291 · see citing works
Rybak, J. M., Muñoz, J. F., Barker, K. S., Parker, J. E., Esquivel, B. D., Berkow, E. L., Lockhart, S. R., Gade, L., Palmer, G. E., White, T. C., et al. (2020) · mBio · doi:10.1128/mbio.00365-20 · Cited by 202 · see citing works
Self-citationCross‐species discovery of syncretic drug combinations that potentiate the antifungal fluconazole
Spitzer, M., Griffiths, E., Blakely, K. M., Wildenhain, J., Ejim, L., Rossi, L., De Pascale, G., Curak, J., Brown, E., Tyers, M., et al. (2011) · Molecular Systems Biology · doi:10.1038/msb.2011.31 · Cited by 183 · see citing works
Nett, J. E., Sanchez, H., Cain, M. T., Ross, K. M., & Andes, D. R. (2011) · Eukaryotic Cell · doi:10.1128/ec.05126-11 · Cited by 168 · see citing works
Candida glabrata Biofilms: How Far Have We Come?
Rodrigues, C., Rodrigues, M., Silva, S., & Henriques, M. (2017) · Journal of Fungi · doi:10.3390/jof3010011 · Cited by 129 · see citing works
Structural basis for species-selective targeting of Hsp90 in a pathogenic fungus
Whitesell, L., Robbins, N., Huang, D. S., McLellan, C. A., Shekhar-Guturja, T., LeBlanc, E. V., Nation, C. S., Hui, R., Hutchinson, A., Collins, C., et al. (2019) · Nature Communications · doi:10.1038/s41467-018-08248-w · Cited by 124 · see citing works
Morschhäuser, J. (2016) · Journal of Microbiology · doi:10.1007/s12275-016-5628-4 · Cited by 118 · see citing works
Molecular basis of antifungal drug resistance in yeasts
Morio, F., Jensen, R. H., Le Pape, P., & Arendrup, M. C. (2017) · International Journal of Antimicrobial Agents · doi:10.1016/j.ijantimicag.2017.05.012 · Cited by 114 · see citing works
Hull, C. M., Parker, J. E., Bader, O., Weig, M., Gross, U., Warrilow, A. G. S., Kelly, D. E., & Kelly, S. L. (2012) · Antimicrobial Agents and Chemotherapy · doi:10.1128/aac.06253-11 · Cited by 113 · see citing works
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Khandelwal, N. K., Chauhan, N., Sarkar, P., Esquivel, B. D., Coccetti, P., Singh, A., Coste, A. T., Gupta, M., Sanglard, D., White, T. C., et al. (2018) · Journal of Biological Chemistry · doi:10.1074/jbc.m117.807032 · Cited by 59 · see citing works
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Transcriptome Signatures Predict Phenotypic Variations of Candida auris
Jenull, S., Tscherner, M., Kashko, N., Shivarathri, R., Stoiber, A., Chauhan, M., Petryshyn, A., Chauhan, N., & Kuchler, K. (2021) · Frontiers in Cellular and Infection Microbiology · doi:10.3389/fcimb.2021.662563 · Cited by 32 · see citing works
- Authors
- Mansfield, B. E., Oltean, H. N., Oliver, B. G., Hoot, S. J., Leyde, S. E., Hedstrom, L., & White, T. C.
- Affiliations
- Center for Infectious Disease Research (US)
- Brandeis University (US)
- Corresponding author
- White, Theodore C.
- Venue
- PLoS Pathogens
- Publisher
- Public Library of Science (PLoS)
- Published
- 2010-09-30
- Volume
- 6
- Issue
- 9
- Pages
- e1001126
- ISSN
- 1553-7366 (ISSN-L)
- 1553-7374
- PMC
- PMC2947996
- OpenAlex
- W1991753849
- Cited by
- 111
- References
- 44
- Citations by year
- 2026: 3 · 2025: 1 · 2024: 2 · 2023: 3 · 2022: 6 · 2021: 4 · 2020: 10 · 2019: 11 · 2018: 6 · 2017: 17 · 2016: 6 · 2015: 9 · 2014: 9 · 2013: 13 · 2012: 4
- FWCI
- 4.77
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- PLoS Pathogens (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Brandeis Institutional Repository (submittedVersion, cc-by)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- University of Washington
- Johns Hopkins University
- National Institutes of Health
- National Institute of Dental and Craniofacial Research (DE14161, DE17078, R01DE011367, DE-11367, R01DE017078, R01DE014161)
- Topics
- Health Sciences › Medicine › Infectious Diseases › Antifungal resistance and susceptibility
- Health Sciences › Medicine › Oncology › Drug Transport and Resistance Mechanisms
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Fungal and yeast genetics research
- Keywords
- azole antifungals, fluconazole, facilitated diffusion, drug importation, Candida albicans, fungal drug resistance, imidazole ring, triazole ring, Cryptococcus neoformans, Saccharomyces cerevisiae, Candida krusei, membrane transporters
- MeSH terms
- Antifungal Agents, Candida albicans, Candidiasis, Cryptococcosis, Cryptococcus neoformans, Diffusion, Humans, Oxygen, Saccharomyces cerevisiae, Fluconazole, Gene Deletion, Drug Resistance, Fungal
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