Mechanisms of Antifungal Drug Resistance

Cowen, Leah E.; Sanglard, Dominique; Howard, Susan J.; Rogers, P. David; Perlin, David S.

doi:10.1101/cshperspect.a019752

Cited by 647Antifungal resistance and susceptibilityFungal and yeast genetics researchFungal Plant Pathogen Control

Mechanisms of Antifungal Drug Resistance

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Cowen, Leah E., Sanglard, Dominique, Howard, Susan J., Rogers, P. David, Perlin, David S.·2015·Cold Spring Harbor Perspectives in Medicine

DOI 10.1101/cshperspect.a019752PMC PMC4484955

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Abstract

Antifungal therapy is a central component of patient management for acute and chronic mycoses. Yet, treatment choices are restricted because of the sparse number of antifungal drug classes. Clinical management of fungal diseases is further compromised by the emergence of antifungal drug resistance, which eliminates available drug classes as treatment options. Once considered a rare occurrence, antifungal drug resistance is on the rise in many high-risk medical centers. Most concerning is the evolution of multidrug- resistant organisms refractory to several different classes of antifungal agents, especially among common Candida species. The mechanisms responsible are mostly shared by both resistant strains displaying inherently reduced susceptibility and those acquiring resistance during therapy. The molecular mechanisms include altered drug affinity and target abundance, reduced intracellular drug levels caused by efflux pumps, and formation of biofilms. New insights into genetic factors regulating these mechanisms, as well as cellular factors important for stress adaptation, provide a foundation to better understand the emergence of antifungal drug resistance.

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Growth conditions influence the degree of tolerance exhibited by a strain.
“In addition to genetic determinants of tolerance level, growth conditions influence the degree of tolerance exhibited by a strain.”
From Drug resistance and tolerance in fungi. (2020) · cites this paper as [68]
The Biofilms section reports that biofilm growth makes normally susceptible planktonic cells highly resistant, supporting the broader point that growth state affects drug response. The Adaptive Cellular Factors section discusses drug tolerance, but our copy does not directly establish that growth conditions change the degree of tolerance exhibited by a given strain. (LLM, conf=0.78)
Experimental — accuracy not yet measured
Calcineurin inhibitors reduce echinocandin tolerance.
“whereas calcineurin inhibitors reduce echinocandin tolerance (measured using MIC assays analyzed after 72 h)68,78.”
From Drug resistance and tolerance in fungi. (2020) · cites this paper as [68]
The Adaptive Cellular Factors section says calcineurin signaling helps fungi survive echinocandin-induced stress, and Drug Resistance Mechanisms reports that calcineurin inhibitors eliminate paradoxical growth at high echinocandin concentrations. This supports reduced tolerance, but our copy does not establish the specified measurement by MIC assays analyzed after 72 hours. (LLM, conf=0.84)
Experimental — accuracy not yet measured
Studies using inhibitors or mutant strains showed that these pathways reduce fungal growth in combination with caspofungin or anidulafungin.
“Specifically, studies of these pathways using either inhibitors or mutant strains showed they reduce fungal growth in combination with caspofungin or anidulafungin.”
From Drug resistance and tolerance in fungi. (2020) · cites this paper as [68]
The Cell Integrity Circuit section reports that deleting pathway genes increases susceptibility to echinocandins and that kinase inhibitors act synergistically with echinocandins against fungi. The Hsp90 section likewise reports reduced echinocandin tolerance after genetic or pharmacological compromise. These passages support the general finding, but do not establish the claimed growth reduction specifically in combination with caspofungin or anidulafungin; they describe inhibiting the pathways, not the pathways themselves reducing growth. (LLM, conf=0.83)
Experimental — accuracy not yet measured
Many core stress response pathways in C. albicans, including Hsp90, Ca2+-calmodulin-calcineurin, lysine deacetylases, protein kinase C and HOG pathways, also affect echinocandin responses.
“Importantly, many of these same core stress response pathways in C. albicans (Hsp90, Ca2+-calmodulin-calcineurin, lysine deacetylases, protein kinase C and HOG (high osmolarity glycerol responses) pathways) t also affect echinocandin responses68,86,87.”
From Drug resistance and tolerance in fungi. (2020) · cites this paper as [68]
The Hsp90, Chitin Synthesis, and Cell Integrity Circuit sections link Hsp90, calcineurin, PKC, and HOG signaling to echinocandin responses in C. albicans. The Hsp90 and Related Factors section discusses lysine deacetylases in relation to C. albicans azole resistance, but does not establish their effect on its echinocandin responses. Page numbers are not available in our copy. (LLM, conf=0.87)
Experimental — accuracy not yet measured
Tolerance is not a function of either uptake or efflux rates.
“but that tolerance is not a function of either uptake or efflux rates, despite the well-known role of efflux in drug resistance [65][66][67][68][69] .”
From Antifungal tolerance is a subpopulation effect distinct from resistance and is associated with persistent candidemia (2018) · cites this paper as [67]

Many infections caused by echinocandin-susceptible C. glabrata or C. albicans isolates do not clear easily.
“In addition, a substantial number of infections with echinocandin-susceptible C. glabrata or C. albicans isolates are not readily cleared68, and the degree to which echinocandin tolerance may play a role in this remains to be determined.”
From Drug resistance and tolerance in fungi. (2020) · cites this paper as [68]
The Adaptive Cellular Factors section discusses echinocandin tolerance but says these stress responses are not typically associated with clinical failures. The Drug Resistance Mechanisms section describes growth of susceptible fungi at high drug concentrations, not whether infections with susceptible C. glabrata or C. albicans isolates clear. A search for clinical outcomes and clearance found no passage establishing the claimed substantial number of difficult-to-clear infections. (LLM, conf=0.72)
Experimental — accuracy not yet measured
ERG3 mutations leading to depletion of ergosterol and accumulation of less toxic sterols when ERG11 is inhibited have been implicated in cross-resistance between azoles and polyenes in S. cerevisiae and C. albicans and between echinocandins and azoles in C. parapsilosis.
“ERG3 mutations leading to the depletion of ergosterol and the accumulation of less toxic sterols when ERG11 is inhibited have been implicated in cross-resistance between azoles and polyenes in S. cerevisiae and C. albicans40, 41, 42, 43 and between echinocandins and azoles in C. parapsilosis.44,45”
From Narrow mutational signatures drive acquisition of multidrug resistance in the fungal pathogen Candida glabrata (2021) · cites this paper as [40]
ERG3 mutations result in reduction of ergosterol and accumulation of other sterols, often leading to cross-resistance to polyenes.
“Furthermore, ERG3 mutations result in the reduction of ergosterol and accumulation of other sterols, often leading to cross-resistance to polyenes [74].”
From Evolutionary Emergence of Drug Resistance in Candida Opportunistic Pathogens (2018) · cites this paper as [74]
Tolerance has both a genetic component, likely involving genes in membrane biosynthesis/integrity and stress response pathways, and an environmental component, as growth conditions have been linked to the degree of tolerance exhibited.
“Tolerance has both a genetic component, likely involving genes in membrane biosynthesis/integrity and the stress response pathways (Cowen et al. 2014; Rosenberg et al. 2018; Berman and Krysan 2020; Todd and Selmecki 2020) and an environmental component, as growth conditions have been linked to the degree of tolerance exhibited (Gerstein et al. 2016; Berman and Krysan 2020).”
From Acquisition of cross-azole tolerance and aneuploidy in Candida albicans strains evolved to posaconazole (2022) · cites this paper as Cowen et al. 2014
The efflux pump system is present in almost all species and plays important roles in drug resistance in bacteria, fungi and human cancer cells by efflux of the drugs.
“The efflux pump system, which is comprised of pumps located in the cell membrane and their regulators, is present in almost all species and plays an important roles in drug resistance in bacteria, fungi and human cancer cells by efflux of the drugs (Golin et al., 2007; Blair et al., 2014; Cowen et al., 2014; Paul and Moye-Rowley, 2014; Tanwar et al., 2014; Kathawala et al., 2015).”
From Abnormal Ergosterol Biosynthesis Activates Transcriptional Responses to Antifungal Azoles (2018) · cites this paper as Cowen et al., 2014

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Molecular Mechanisms of Drug Resistance in Clinical Candida Species Isolated from Tunisian Hospitals
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Biofilms and their Role in the Resistance of Pathogenic Candida to Antifungal Agents
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Lysine Deacetylases Hda1 and Rpd3 Regulate Hsp90 Function thereby Governing Fungal Drug Resistance
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The yeast zinc finger regulators Pdr1p and Pdr3p control pleiotropic drug resistance (PDR) as homo‐ and heterodimers in vivo
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Genome-Wide Expression and Location Analyses of the Candida albicans Tac1p Regulon
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Genomic Approach to Identification of Mutations Affecting Caspofungin Susceptibility in Saccharomyces cerevisiae
Markovich, S., Yekutiel, A., Shalit, I., Shadkchan, Y., & Osherov, N. (2004) · Antimicrobial Agents and Chemotherapy · doi:10.1128/aac.48.10.3871-3876.2004 · Cited by 122 · see citing works
Identification of a Cryptococcus neoformans Cytochrome P450 Lanosterol 14α-Demethylase (Erg11) Residue Critical for Differential Susceptibility between Fluconazole/Voriconazole and Itraconazole/Posaconazole
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Candida albicans biofilms: building a heterogeneous, drug-tolerant environment
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Evaluation of fluconazole resistance mechanisms in candida albicans clinical isolates from HIV-infected patients in Brazil
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Differential In Vivo Activities of Anidulafungin, Caspofungin, and Micafungin against Candida glabrata Isolates with and without FKS Resistance Mutations
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Identification of the Candida albicans Cap1p Regulon
Znaidi, S., Barker, K. S., Weber, S., Alarco, A.-M., Liu, T. T., Boucher, G., Rogers, P. D., & Raymond, M. (2009) · Eukaryotic Cell · doi:10.1128/ec.00002-09 · Cited by 115 · see citing works
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Discovery of Cercosporamide, a Known Antifungal Natural Product, as a Selective Pkc1 Kinase Inhibitor through High-Throughput Screening
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Potent Synergistic Effect of Doxycycline with Fluconazole against Candida albicans Is Mediated by Interference with Iron Homeostasis
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Azole heteroresistance in Cryptococcus neoformans: Emergence of resistant clones with chromosomal disomy in the mouse brain during fluconazole treatment
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Azole Drugs Are Imported By Facilitated Diffusion in Candida albicans and Other Pathogenic Fungi
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A 1-year prospective survey of candidemia in Italy and changing epidemiology over one decade
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Contribution of CgPDR1-Regulated Genes in Enhanced Virulence of Azole-Resistant Candida glabrata
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Rapid Acquisition of Stable Azole Resistance by Candida glabrata Isolates Obtained before the Clinical Introduction of Fluconazole
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Pharmacokinetics and Pharmacodynamics of Posaconazole for Invasive Pulmonary Aspergillosis: Clinical Implications for Antifungal Therapy
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Inducible Azole Resistance Associated with a Heterogeneous Phenotype in Candida albicans
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MFS transportome of the human pathogenic yeast Candida albicans
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Isolation of a Putative Candida albicans Transcriptional Regulator Involved in Pleiotropic Drug Resistance by Functional Complementation of a pdr1 pdr3 Mutation in Saccharomyces cerevisiae
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Small but Crucial: The Novel Small Heat Shock Protein Hsp21 Mediates Stress Adaptation and Virulence in Candida albicans
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Assessment of the Paradoxical Effect of Caspofungin in Therapy of Candidiasis
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Genetic Dissection of Azole Resistance Mechanisms in Candida albicans and Their Validation in a Mouse Model of Disseminated Infection
MacCallum, D. M., Coste, A., Ischer, F., Jacobsen, M. D., Odds, F. C., & Sanglard, D. (2010) · Antimicrobial Agents and Chemotherapy · doi:10.1128/aac.01645-09 · Cited by 98 · see citing works
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Multiple resistance mechanisms to azole antifungals in yeast clinical isolates
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Multiple Resistant Phenotypes of Candida albicans Coexist during Episodes of Oropharyngeal Candidiasis in Human Immunodeficiency Virus-Infected Patients
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Azole Susceptibility and Transcriptome Profiling in Candida albicans Mitochondrial Electron Transport Chain Complex I Mutants
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“However, pharmacological inhibition of mitochondrial complexes involved in respiration and energy production results in higher susceptibility to azoles in this species (Sun et al. 2013).”
Background
CaNdt80 Is Involved in Drug Resistance in Candida albicans by Regulating CDR1
Chen, C.-G., Yang, Y.-L., Shih, H., Su, C.-L., & Lo, H. (2004) · Antimicrobial Agents and Chemotherapy · doi:10.1128/aac.48.12.4505-4512.2004 · Cited by 94 · see citing works
A toolbox for epitope-tagging and genome-wide location analysis in Candida albicans
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The fungal Achilles’ heel: targeting Hsp90 to cripple fungal pathogens
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Genomewide Expression Profile Analysis of the Candida glabrata Pdr1 Regulon
Caudle, K. E., Barker, K. S., Wiederhold, N. P., Xu, L., Homayouni, R., & Rogers, P. D. (2010) · Eukaryotic Cell · doi:10.1128/ec.00073-10 · Cited by 92 · see citing works
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New Fks Hot Spot for Acquired Echinocandin Resistance in Saccharomyces cerevisiae and Its Contribution to Intrinsic Resistance of Scedosporium Species
Johnson, M. E., Katiyar, S. K., & Edlind, T. D. (2011) · Antimicrobial Agents and Chemotherapy · doi:10.1128/aac.01811-10 · Cited by 91 · see citing works
Role of Ndt80p in Sterol Metabolism Regulation and Azole Resistance in Candida albicans
Sellam, A., Tebbji, F., & Nantel, A. (2009) · Eukaryotic Cell · doi:10.1128/ec.00074-09 · Cited by 91 · see citing works
Overexpression of the MDR1 Gene Is Sufficient To Confer Increased Resistance to Toxic Compounds in Candida albicans
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Antifungal Combinations against Candida albicans Biofilms In Vitro
Bachmann, S. P., Ramage, G., VandeWalle, K., Patterson, T. F., Wickes, B. L., & López-Ribot, J. L. (2003) · Antimicrobial Agents and Chemotherapy · doi:10.1128/aac.47.11.3657-3659.2003 · Cited by 89 · see citing works
In-vivo selection of an azole-resistant petite mutant of Candida glabrata
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Environmental fungicides and triazole resistance in Aspergillus
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Genome-wide Mapping of the Coactivator Ada2p Yields Insight into the Functional Roles of SAGA/ADA Complex inCandida albicans
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The yeast FKS1 gene encodes a novel membrane protein, mutations in which confer FK506 and cyclosporin A hypersensitivity and calcineurin-dependent growth
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Regulatory Role of Glycerol in Candida albicans Biofilm Formation
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The Hsp90 Co-Chaperone Sgt1 Governs Candida albicans Morphogenesis and Drug Resistance
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Analysis of a fungus‐specific transcription factor family, the <scp>C</scp>andida albicans zinc cluster proteins, by artificial activation
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Microarray and Molecular Analyses of the Azole Resistance Mechanism in Candida glabrata Oropharyngeal Isolates
Tsai, H.-F., Sammons, L. R., Zhang, X., Suffis, S. D., Su, Q., Myers, T. G., Marr, K. A., & Bennett, J. E. (2010) · Antimicrobial Agents and Chemotherapy · doi:10.1128/aac.00535-10 · Cited by 80 · see citing works
<scp>CRS–MIS</scp> in <scp>C</scp>andida glabrata: sphingolipids modulate echinocandin–<scp>Fks</scp> interaction
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Evolution by Any Other Name: Antibiotic Resistance and Avoidance of the E-Word
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Functional Analysis of cis - and trans -Acting Elements of the Candida albicans CDR2 Promoter with a Novel Promoter Reporter System
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Regulation of the CgPdr1 Transcription Factor from the Pathogen Candida glabrata
Paul, S., Schmidt, J. A., & Moye-Rowley, W. S. (2011) · Eukaryotic Cell · doi:10.1128/ec.00277-10 · Cited by 78 · see citing works
Identification of a Key Lysine Residue in Heat Shock Protein 90 Required for Azole and Echinocandin Resistance in Aspergillus fumigatus
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Complex Interplay Among Regulators of Drug Resistance Genes in Saccharomyces cerevisiae
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Identification of promoter elements responsible for the regulation of MDR1 from Candida albicans, a major facilitator transporter involved in azole resistance
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Candida glabrataOropharyngeal Candidiasis in Patients Receiving Radiation Treatment for Head and Neck Cancer
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Topological and Mutational Analysis of Saccharomyces cerevisiae Fks1
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Increases in SLT2 Expression and Chitin Content Are Associated with Incomplete Killing of Candida glabrata by Caspofungin
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Fungal Biofilms and Antimycotics
Chandra, J., Zhou, G., & Ghannoum, M. A. (2005) · Current Drug Targets · doi:10.2174/138945005774912762 · Cited by 69 · see citing works
Role for Fks1 in the Intrinsic Echinocandin Resistance of Fusarium solani as Evidenced by Hybrid Expression in Saccharomyces cerevisiae
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Triazole fungicides and the selection of resistance to medical triazoles in the opportunistic mould Aspergillus fumigatus
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Emergence of Azole Resistance in Aspergillus fumigatus and Spread of a Single Resistance Mechanism.
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Chitin Synthases with a Myosin Motor-Like Domain Control the Resistance of Aspergillus fumigatus to Echinocandins
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Persistent Candida albicans colonization and molecular mechanisms of azole resistance in autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED) patients
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Paradoxical effect of caspofungin against Candida bloodstream isolates is mediated by multiple pathways but eliminated in human serum
Shields, R. K., Nguyen, M. H., Du, C., Press, E., Cheng, S., & Clancy, C. J. (2011) · Antimicrobial Agents and Chemotherapy · doi:10.1128/aac.00999-10 · Cited by 65 · see citing works
Proteomic analysis of experimentally induced azole resistance in Candida glabrata
Rogers, P. D. (2006) · Journal of Antimicrobial Chemotherapy · doi:10.1093/jac/dkl221 · Cited by 64 · see citing works
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The global problem of antifungal resistance: prevalence, mechanisms, and management
Perlin, D. S., Rautemaa-Richardson, R., & Alastruey-Izquierdo, A. (2017) · The Lancet Infectious Diseases · doi:10.1016/s1473-3099(17)30316-x · Cited by 1,055 · see citing works
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Drug resistance and tolerance in fungi.
Berman, J., & Krysan, D. J. (2020) · Nature Reviews Microbiology · doi:10.1038/s41579-019-0322-2 · Cited by 654 · see citing works
Antifungal Therapy: New Advances in the Understanding and Treatment of Mycosis
Scorzoni, L., de Paula e Silva, A. C. A., Marcos, C. M., Assato, P. A., de Melo, W. C. M. A., de Oliveira, H. C., Costa-Orlandi, C. B., Mendes-Giannini, M. J. S., & Fusco-Almeida, A. M. (2017) · Frontiers in Microbiology · doi:10.3389/fmicb.2017.00036 · Cited by 418 · see citing works
Echinocandin resistance in Candida.
Perlin, D. S. (2015) · Clinical Infectious Diseases · doi:10.1093/cid/civ791 · Cited by 374 · see citing works
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Antifungal tolerance is a subpopulation effect distinct from resistance and is associated with persistent candidemia
Rosenberg, A., Ene, I. V., Bibi, M., Zakin, S., Segal, E. S., Ziv, N., Dahan, A. M., Colombo, A. L., Bennett, R. J., & Berman, J. (2018) · Nature Communications · doi:10.1038/s41467-018-04926-x · Cited by 270 · see citing works
Prevalent mutator genotype identified in fungal pathogen Candida glabrata promotes multi-drug resistance.
Healey, K. R., Zhao, Y., Perez, W. B., Lockhart, S. R., Sobel, J. D., Farmakiotis, D., Kontoyiannis, D. P., Sanglard, D., Taj-Aldeen, S. J., Alexander, B. D., et al. (2016) · Nature Communications · doi:10.1038/ncomms11128 · Cited by 276 · see citing works
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Evolutionary Emergence of Drug Resistance in Candida Opportunistic Pathogens
Ksiezopolska, E., & Gabaldón, T. (2018) · Genes · doi:10.3390/genes9090461 · Cited by 230 · see citing works
Fungal Resistance to Echinocandins and the MDR Phenomenon in Candida glabrata
Healey, K. R., & Perlin, D. S. (2018) · Journal of Fungi · doi:10.3390/jof4030105 · Cited by 194 · see citing works
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Limited ERG11 Mutations Identified in Isolates of Candida auris Directly Contribute to Reduced Azole Susceptibility
Healey, K. R., Kordalewska, M., Jiménez Ortigosa, C., Singh, A., Berrío, I., Chowdhary, A., & Perlin, D. S. (2018) · Antimicrobial Agents and Chemotherapy · doi:10.1128/aac.01427-18 · Cited by 165 · see citing works
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Expandable and reversible copy number amplification drives rapid adaptation to antifungal drugs
Todd, R. T., & Selmecki, A. (2020) · eLife · doi:10.7554/elife.58349 · Cited by 138 · see citing works
The Quiet and Underappreciated Rise of Drug-Resistant Invasive Fungal Pathogens
Arastehfar, A., Lass-Flörl, C., Garcia-Rubio, R., Daneshnia, F., Ilkit, M., Boekhout, T., Gabaldon, T., & Perlin, D. S. (2020) · Journal of Fungi · doi:10.3390/jof6030138 · Cited by 145 · see citing works
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Ibrexafungerp: A First-in-Class Oral Triterpenoid Glucan Synthase Inhibitor
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Defining the frontiers between antifungal resistance, tolerance and the concept of persistence
Delarze, E., & Sanglard, D. (2015) · Drug Resistance Updates · doi:10.1016/j.drup.2015.10.001 · Cited by 118 · see citing works
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Candida parapsilosis Resistance to Fluconazole: Molecular Mechanisms and In Vivo Impact in Infected Galleria mellonella Larvae
Souza, A. C. R., Fuchs, B. B., Pinhati, H. M. S., Siqueira, R. A., Hagen, F., Meis, J. F., Mylonakis, E., & Colombo, A. L. (2015) · Antimicrobial Agents and Chemotherapy · doi:10.1128/aac.01177-15 · Cited by 121 · see citing works
Inflammasome-mediated GSDMD activation facilitates escape of Candida albicans from macrophages
Ding, X., Kambara, H., Guo, R., Kanneganti, A., Acosta-Zaldívar, M., Li, J., Liu, F., Bei, T., Qi, W., Xie, X., et al. (2021) · Nature Communications · doi:10.1038/s41467-021-27034-9 · Cited by 115 · see citing works
Abnormal Ergosterol Biosynthesis Activates Transcriptional Responses to Antifungal Azoles
Hu, C., Zhou, M., Wang, W., Sun, X., Yarden, O., & Li, S. (2018) · Frontiers in Microbiology · doi:10.3389/fmicb.2018.00009 · Cited by 114 · see citing works
Narrow mutational signatures drive acquisition of multidrug resistance in the fungal pathogen Candida glabrata
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Authors: Cowen, L. E., Sanglard, D., Howard, S. J., Rogers, P. D., & Perlin, D. S.
Affiliations: University of Toronto (CA)
Centre Hospitalier Universitaire Vaudois (CH)
University of Liverpool (GB)
University of Tennessee Health Science Center (US)
Rutgers, The State University of New Jersey (US)
ORCID: Cowen, Leah E.
Sanglard, Dominique
Rogers, P. David
Perlin, David S.
Venue: Cold Spring Harbor Perspectives in Medicine
Publisher: Cold Spring Harbor Laboratory
Published: 2014-11-10
Volume: 5
Issue: 7
Pages: a019752
ISSN: 2157-1422 (ISSN-L)
DOI: 10.1101/cshperspect.a019752
PMC: PMC4484955
OpenAlex: W2136677555
Cited by: 647
References: 222
Citations by year: 2026: 55 · 2025: 64 · 2024: 79 · 2023: 77 · 2022: 78 · 2021: 74 · 2020: 71 · 2019: 53 · 2018: 40 · 2017: 21 · 2016: 23 · 2015: 12
Type: posted content
Language: en
Open access: bronze
doi.org
Locations: Cold Spring Harbor Perspectives in Medicine (publishedVersion)
PubMed Central (publishedVersion)
PubMed (publishedVersion)
IRIS (submittedVersion)
SERVAL (Université de Lausanne) (submittedVersion)
Funders: National Institutes of Health (2r01ai109025-11)
National Institute of Allergy and Infectious Diseases (R01AI058145, R01AI-109025)
Topics: Health Sciences › Medicine › Infectious Diseases › Antifungal resistance and susceptibility
Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Fungal and yeast genetics research
Life Sciences › Agricultural and Biological Sciences › Ecology, Evolution, Behavior and Systematics › Fungal Plant Pathogen Control
Keywords: antifungal resistance, Candida, multidrug resistance, efflux pumps, biofilm, drug target alterations, stress adaptation, fungal infection, acquired resistance, molecular mechanisms of resistance
MeSH terms: Antifungal Agents, Humans, Mycoses, Biofilms, RNA Stability, Drug Resistance, Fungal

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