Fluconazole-Induced Ploidy Change in Cryptococcus neoformans Results from the Uncoupling of Cell Growth and Nuclear Division
Open accessAbstract
Azoles are antifungals that are widely utilized due to relatively low toxicity and cost of treatment. One of their drawbacks, however, is that azoles are primarily cytostatic, leaving fungal cells capable of developing drug resistance. The human pathogen Cryptococcus neoformans acquires resistance to the azole drug fluconazole (FLC) through the development of aneuploidy, leading to elevated expression of key resistance genes, a mechanism that is also common for Candida albicans (K. J. Kwon-Chung and Y. C. Chang, PLoS Pathog 8:e1003022, 2012, https://doi.org/10.1371/journal.ppat.1003022 ; J. Morschhäuser, J Microbiol 54:192–201, 2016, https://doi.org/10.1007/s12275-016-5628-4 ). However, the exact ways in which FLC contributes to increased resistance in either of these important fungal pathogens remain unclear. Here we found that FLC treatment leads to an increase in DNA content in C. neoformans through multiple mechanisms, potentially increasing the size of a pool of cells from which aneuploids with increased resistance are selected. This study demonstrated the importance of FLC’s inhibitory effects on growth and cytokinesis in the generation of cell populations with decreased sensitivity to the drug.
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Exposure to inhibitory concentrations of fluconazole diminished budding and growth while permitting nuclear events, resulting in populations with increased DNA that grow better in the presence of fluconazole, increasing aneuploidy and survival.
“Other research on C. neoformans’ ploidy found that exposure to inhibitory concentrations of fluconazole diminished budding and growth while permitting nuclear events. This resulted in populations with increased DNA, whose content grow better in the presence of fluconazole, increasing aneuploidy and survival [161].”
From Insight into the Mechanisms and Clinical Relevance of Antifungal Heteroresistance (2025) · cites this paper as [161]
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Experimental — accuracy not yet measuredResearch suggests that either mis-segregation of chromosomes or compromised nuclear division leads to the formation of aneuploid cells under azole stress.
“research suggests that either mis-segregation of chromosomes or compromised nuclear division leads to the formation of aneuploid cells under azole stress27–29.”
From Treatment strategies for cryptococcal infection: challenges, advances and future outlook (2021) · cites this paper as [27]
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Cites
The ImageJ ecosystem: An open platform for biomedical image analysis
Schindelin, J., Rueden, C., Hiner, M., & Eliceiri, K. W. (2015) · Molecular Reproduction and Development · doi:10.1002/mrd.22489 · Cited by 2,646 · see citing works
Ayscough, K. R., Stryker, J., Pokala, N., Sanders, M. L., Crews, P., & Drubin, D. G. (1997) · The Journal of Cell Biology · doi:10.1083/jcb.137.2.399 · Cited by 736 · see citing works
Weaver, B. A. A., & Cleveland, D. W. (2006) · Current Opinion in Cell Biology · doi:10.1016/j.ceb.2006.10.002 · Cited by 560 · see citing works
Sionov, E., Lee, H., Chang, Y. C., & Kwon-Chung, K. J. (2010) · PLoS Pathogens · doi:10.1371/journal.ppat.1000848 · Cited by 479 · see citing works
Architecture and Biosynthesis of the Saccharomyces cerevisiae Cell Wall
Orlean, P. (2012) · Genetics · doi:10.1534/genetics.112.144485 · Cited by 479 · see citing works
Genome-wide genetic analysis of polyploidy in yeast
Štorchová, Z., Breneman, A., Cande, J., Dunn, J. G., Burbank, K. S., O'Toole, E. T., & Pellman, D. S. (2006) · Nature · doi:10.1038/nature05178 · Cited by 360 · see citing works
Cryptococcal cell morphology affects host cell interactions and pathogenicity
Okagaki, L. H., Strain, A. K., Nielsen, J. N., Charlier, C., Baltes, N. J., Chrétien, F., Heitman, J., Dromer, F., & Nielsen, K. (2010) · PLoS Pathogens · doi:10.1371/journal.ppat.1000953 · Cited by 345 · see citing works
Genomic Plasticity of the Human Fungal Pathogen Candida albicans
Selmecki, A., Forche, A., & Berman, J. (2010) · Eukaryotic Cell · doi:10.1128/ec.00060-10 · Cited by 247 · see citing works
Banks, I. R., Specht, C. A., Donlin, M. J., Gerik, K. J., Levitz, S. M., & Lodge, J. K. (2005) · Eukaryotic Cell · doi:10.1128/ec.4.11.1902-1912.2005 · Cited by 245 · see citing works
Requirement for Ergosterol in V-ATPase Function Underlies Antifungal Activity of Azole Drugs
Zhang, Y.-Q., Gamarra, S., Garcia-Effron, G., Park, S., Perlin, D. S., & Rao, R. (2010) · PLoS Pathogens · doi:10.1371/journal.ppat.1000939 · Cited by 206 · see citing works
Gene Disruption by Biolistic Transformation in Serotype D Strains of Cryptococcus neoformans
Davidson, R. C., Cruz, M. C., Sia, R. A. L., Allen, B., Alspaugh, J. A., & Heitman, J. (2000) · Fungal Genetics and Biology · doi:10.1006/fgbi.1999.1180 · Cited by 194 · see citing works
Karyotyping of Cryptococcus neoformans as an epidemiological tool
Perfect, J. R., Ketabchi, N., Cox, G. M., Ingram, C. W., & Beiser, C. L. (1993) · Journal of Clinical Microbiology · doi:10.1128/jcm.31.12.3305-3309.1993 · Cited by 184 · see citing works
A Tetraploid Intermediate Precedes Aneuploid Formation in Yeasts Exposed to Fluconazole
Harrison, B. D., Hashemi, J., Bibi, M., Pulver, R., Bavli, D., Nahmias, Y., Wellington, M., Sapiro, G., & Berman, J. (2014) · PLoS Biology · doi:10.1371/journal.pbio.1001815 · Cited by 174 · see citing works
Polyploid titan cells produce haploid and aneuploid progeny to promote stress adaptation
Gerstein, A. C., Fu, M. S., Mukaremera, L., Li, Z., Ormerod, K. L., Fraser, J. A., Berman, J., & Nielsen, K. (2015) · mBio · doi:10.1128/mbio.01340-15 · Cited by 167 · see citing works
High levels of chromosome instability in polyploids of Saccharomyces cerevisiae
Mayer, V. W., & Aguilera, A. (1990) · Mutation research. Fundamental and molecular mechanisms of mutagenesis · doi:10.1016/0027-5107(90)90024-x · Cited by 160 · see citing works
Cytochrome P450 of Fungi: Primary Target for Azole Antifungal Agents
Yoshida, Y. (1988) · Current topics in medical mycology · doi:10.1007/978-1-4612-3730-3_11 · Cited by 143 · see citing works
Cholesterol is essential for mitosis progression and its deficiency induces polyploid cell formation
Fernández, C., Toledo-Lobo, M. V., Gómez‐Coronado, D., & Lasunción, M. A. (2004) · Experimental Cell Research · doi:10.1016/j.yexcr.2004.06.029 · Cited by 141 · see citing works
Lin, X., Patel, S., Litvintseva, A. P., Floyd, A. M., Mitchell, T. G., & Heitman, J. (2009) · PLoS Pathogens · doi:10.1371/journal.ppat.1000283 · Cited by 120 · see citing works
Sionov, E., Chang, Y. C., & Kwon-Chung, K. J. (2013) · Antimicrobial Agents and Chemotherapy · doi:10.1128/aac.00694-13 · Cited by 112 · see citing works
Mixed Infections and In Vivo Evolution in the Human Fungal Pathogen Cryptococcus neoformans
Desnos‐Ollivier, M., Patel, S., Spaulding, A. R., et al. (2010) · mBio · doi:10.1128/mbio.00091-10 · Cited by 98 · see citing works
Kozubowski, L., & Heitman, J. (2009) · Molecular Microbiology · doi:10.1111/j.1365-2958.2009.06983.x · Cited by 89 · see citing works
Self-citationPloidy plasticity: a rapid and reversible strategy for adaptation to stress
Berman, J. G. (2016) · FEMS Yeast Research · doi:10.1093/femsyr/fow020 · Cited by 80 · see citing works
Aneuploidy and Drug Resistance in Pathogenic Fungi
Kwon-Chung, K. J., & Chang, Y. C. (2012) · PLoS Pathogens · doi:10.1371/journal.ppat.1003022 · Cited by 76 · see citing works
Fluconazole resistance in cryptococcal disease: emerging or intrinsic?
Cheong, J. W. S., & McCormack, J. (2012) · Medical Mycology · doi:10.3109/13693786.2012.715763 · Cited by 75 · see citing works
Fluconazole tolerance in clinical isolates of Cryptococcus neoformans
Venkateswarlu, K., Taylor, M., Manning, N. J., Rinaldi, M. G., & Kelly, S. L. (1997) · Antimicrobial Agents and Chemotherapy · doi:10.1128/aac.41.4.748 · Cited by 74 · see citing works
Constitutive mosaic aneuploidy is a unique genetic feature widespread in the Leishmania genus
Lachaud, L., Bourgeois, N., Kuk, N., Morelle, C., Crobu, L., Merlin, G., Bastien, P., Pagès, M., & Sterkers, Y. (2013) · Microbes and Infection · doi:10.1016/j.micinf.2013.09.005 · Cited by 74 · see citing works
Ploidy variation as an adaptive mechanism in human pathogenic fungi
Morrow, C. A., & Fraser, J. A. (2013) · Seminars in Cell and Developmental Biology · doi:10.1016/j.semcdb.2013.01.008 · Cited by 72 · see citing works
Walton, F. J., Heitman, J., & Idnurm, A. (2006) · Molecular Biology of the Cell · doi:10.1091/mbc.e06-02-0125 · Cited by 69 · see citing works
Ordered Kinetochore Assembly in the Human-Pathogenic Basidiomycetous Yeast Cryptococcus neoformans
Kozubowski, L., Yadav, V., Chatterjee, G., et al. (2013) · mBio · doi:10.1128/mbio.00614-13 · Cited by 57 · see citing works
Self-citationMethods for comparing Salmonella mutagenicity data sets using nonlinear models
Alvord, W. G., Driver, J., Claxton, L. D., et al. (1990) · Mutation Research/Genetic Toxicology · doi:10.1016/0165-1218(90)90057-9 · Cited by 53 · see citing works
Fox, D. S., Cox, G. M., & Heitman, J. (2003) · Eukaryotic Cell · doi:10.1128/ec.2.5.1025-1035.2003 · Cited by 47 · see citing works
Shift and adapt: the costs and benefits of karyotype variations
Gerstein, A. C., & Berman, J. G. (2015) · Current Opinion in Microbiology · doi:10.1016/j.mib.2015.06.010 · Cited by 40 · see citing works
Lin, X., Patel, S., Litvintseva, A. P., et al. (2009) · Cited by 39 · see citing works
Chitinases Are Essential for Sexual Development but Not Vegetative Growth in Cryptococcus neoformans
Baker, L. G., Specht, C. A., & Lodge, J. K. (2009) · Eukaryotic Cell · doi:10.1128/ec.00227-09 · Cited by 36 · see citing works
Fluconazole: A New Triazole Antifungal Agent
Morrow, J. D. (1991) · The American Journal of the Medical Sciences · doi:10.1097/00000441-199108000-00012 · Cited by 35 · see citing works
Cytological Study of Cell Cycle of the Pathogenic Yeast Cryptococcus neoformans
Yamaguchi, M., Ohkusu, M., Biswas, S. K., et al. (2007) · Nippon Ishinkin Gakkai Zasshi · doi:10.3314/jjmm.48.147 · Cited by 27 · see citing works
A comprehensive model to predict mitotic division in budding yeasts
Sutradhar, S., Yadav, V., Sridhar, S., Sreekumar, L., Bhattacharyya, D., Ghosh, S., Paul, R., & Sanyal, K. (2015) · Molecular Biology of the Cell · doi:10.1091/mbc.e15-04-0236 · Cited by 24 · see citing works
Self-citationAboobakar, E. F., Wang, X., Heitman, J., & Kozubowski, L. (2011) · Eukaryotic Cell · doi:10.1128/ec.05148-11 · Cited by 17 · see citing works
Self-citationMechanisms of cytokinesis in basidiomycetous yeasts
Altamirano, S., Chandrasekaran, S., & Kozubowski, L. (2017) · Fungal Biology Reviews · doi:10.1016/j.fbr.2016.12.002 · Cited by 3 · see citing works
Self-citation
Flagged first, then by citations
Cited by
Sorted by citations
Treatment strategies for cryptococcal infection: challenges, advances and future outlook
Iyer, K. R., Revie, N. M., Fu, C., Robbins, N., & Cowen, L. E. (2021) · Nature Reviews Microbiology · doi:10.1038/s41579-021-00511-0 · Cited by 363 · see citing works
Dambuza, I. M., Drake, T., Chapuis, A., Zhou, X., Correia, J., Taylor-Smith, L., LeGrave, N., Rasmussen, T., Fisher, M. C., Bicanic, T., et al. (2018) · PLoS Pathogens · doi:10.1371/journal.ppat.1006978 · Cited by 182 · see citing works
Dynamic ploidy changes drive fluconazole resistance in human cryptococcal meningitis
Stone, N. R. H., Rhodes, J., Fisher, M. C., Mfinanga, S., Kivuyo, S., Rugemalila, J., Segal, E. S., Needleman, L., Molloy, S. F., Kwon-Chung, J., et al. (2019) · Journal of Clinical Investigation · doi:10.1172/jci124516 · Cited by 167 · see citing works
Aneuploidy Enables Cross-Adaptation to Unrelated Drugs
Yang, F., Teoh, F., Tan, A. S. M., Cao, Y., Pavelka, N., & Berman, J. (2019) · Molecular Biology and Evolution · doi:10.1093/molbev/msz104 · Cited by 101 · see citing works
A titanic drug resistance threat in Cryptococcus neoformans
Zafar, H., Altamirano, S., Ballou, E. R., & Nielsen, K. (2019) · Current Opinion in Microbiology · doi:10.1016/j.mib.2019.11.001 · Cited by 76 · see citing works
Self-citationHope, W., Stone, N. R. H., Johnson, A., McEntee, L., Farrington, N., Santoro-Castelazo, A., Liu, X., Lucaci, A., Hughes, M., Oliver, J. D., et al. (2019) · mBio · doi:10.1128/mbio.02575-19 · Cited by 70 · see citing works
A Double-Edged Sword: Aneuploidy is a Prevalent Strategy in Fungal Adaptation
Tsai, H.-J., & Nelliat, A. (2019) · Genes · doi:10.3390/genes10100787 · Cited by 60 · see citing works
Yang, F., Scopel, E. F. C., Li, H., Sun, L.-L., Kawar, N., Cao, Y.-B., Jiang, Y.-Y., & Berman, J. (2023) · mBio · doi:10.1128/mbio.00227-23 · Cited by 62 · see citing works
Yang, F., Gritsenko, V., Lu, H., Zhen, C., Gao, L., Berman, J., & Jiang, Y.-Y. (2021) · Microbiology Spectrum · doi:10.1128/spectrum.00723-21 · Cited by 49 · see citing works
Chang, Y. C., Khanal Lamichhane, A., & Kwon-Chung, K. J. (2018) · mBio · doi:10.1128/mbio.01290-18 · Cited by 34 · see citing works
Altamirano, S., Simmons, C., & Kozubowski, L. (2018) · Frontiers in Cellular and Infection Microbiology · doi:10.3389/fcimb.2018.00203 · Cited by 19 · see citing works
Self-citationInsight into the Mechanisms and Clinical Relevance of Antifungal Heteroresistance
Su, Y., Li, Y., Yi, Q., Xu, Y., Sun, T., & Li, Y. (2025) · Journal of Fungi · doi:10.3390/jof11020143 · Cited by 18 · see citing works
“This resulted in populations with increased DNA, whose content grow better in the presence of fluconazole, increasing aneuploidy and survival [161].”
- Authors
- Altamirano, S., Fang, D., Simmons, C., Sridhar, S., Wu, P., Sanyal, K., & Kozubowski, L.
- Affiliations
- Clemson University (US)
- Jawaharlal Nehru Centre for Advanced Scientific Research (IN)
- Corresponding author
- Kozubowski, Lukasz
- Venue
- mSphere
- Publisher
- American Society for Microbiology
- Published
- 2017-06-28
- Volume
- 2
- Issue
- 3
- ISSN
- 2379-5042 (ISSN-L)
- PMC
- PMC5471349
- OpenAlex
- W2626773521
- Cited by
- 46
- References
- 39
- Citations by year
- 2026: 6 · 2025: 5 · 2024: 1 · 2023: 1 · 2022: 3 · 2021: 7 · 2020: 4 · 2019: 10 · 2018: 8 · 2017: 1
- FWCI
- 4.93
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- mSphere (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- HHS | NIH | NIH Office of the Director (1R15 AI119801-01)
- Topics
- Health Sciences › Medicine › Epidemiology › Fungal Infections and Studies
- Health Sciences › Medicine › Infectious Diseases › Antifungal resistance and susceptibility
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Fungal and yeast genetics research
- Keywords
- fluconazole, Cryptococcus neoformans, aneuploidy, azole resistance, drug resistance, cytokinesis, cell growth, DNA content, antifungal agents, cytostatic activity, fungal pathogens
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