Stepwise emergence of azole, echinocandin and amphotericin B multidrug resistance in vivo in Candida albicans orchestrated by multiple genetic alterations
Open accessAbstract
OBJECTIVES: The objective of this study was to characterize the underlying molecular mechanisms in consecutive clinical Candida albicans isolates from a single patient displaying stepwise-acquired multidrug resistance. METHODS: Nine clinical isolates (P-1 to P-9) were susceptibility tested by EUCAST EDef 7.2 and Etest. P-4, P-5, P-7, P-8 and P-9 were available for further studies. Relatedness was evaluated by MLST. Additional genes were analysed by sequencing (including FKS1, ERG11, ERG2 and TAC1) and gene expression by quantitative PCR (CDR1, CDR2 and ERG11). UV-spectrophotometry and GC-MS were used for sterol analyses. In vivo virulence was determined in the insect model Galleria mellonella and evaluated by log-rank Mantel-Cox tests. RESULTS: P-1 + P-2 were susceptible, P-3 + P-4 fluconazole resistant, P-5 pan-azole resistant, P-6 + P-7 pan-azole and echinocandin resistant and P-8 + P-9 MDR. MLST supported genetic relatedness among clinical isolates. P-4 harboured four changes in Erg11 (E266D, G307S, G450E and V488I), increased expression of ERG11 and CDR2 and a change in Tac1 (R688Q). P-5, P-7, P-8 and P-9 had an additional change in Erg11 (A61E), increased expression of CDR1, CDR2 and ERG11 (except for P-7) and a different amino acid change in Tac1 (R673L). Echinocandin-resistant isolates harboured the Fks1 S645P alteration. Polyene-resistant P-8 + P-9 lacked ergosterol and harboured a frameshift mutation in ERG2 (F105SfsX23). Virulence was attenuated (but equivalent) in the clinical isolates, but higher than in the azole- and echinocandin-resistant unrelated control strain. CONCLUSIONS: C. albicans demonstrates a diverse capacity to adapt to antifungal exposure. Potentially novel resistance-inducing mutations in TAC1, ERG11 and ERG2 require independent validation.
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Multidrug resistance is not restricted to C. glabrata or C. auris; other examples include C. kefyr, C. lusitaniae, and C. albicans.
“However, MDR is not restricted to C. glabrata or C. auris. Other examples include C. kefyr [57], C. lusitaniae [58], and C. albicans [59,60,61].”
From Evolutionary Emergence of Drug Resistance in Candida Opportunistic Pathogens (2018) · cites this paper as [61]
Lower abundance of the enzyme has been observed in polyene-resistant species and attributed to mutations in ERG2, ERG3, ERG5, ERG6, and ERG11 genes.
“Lower abundance of the enzyme has been observed in polyene-resistant species, which has been attributed to mutations in ERG2 [61,112], ERG3 [51], ERG5 [60], ERG6 [113], and ERG11 [60] genes, which encode enzymes involved in ergosterol synthesis.”
From Evolutionary Emergence of Drug Resistance in Candida Opportunistic Pathogens (2018) · cites this paper as [61]
Candida strains resistant to amphotericin B were found to harbor mutations in ERG2, ERG3, ERG5, and ERG11, and were co-resistant to fluconazole.
“Candida strains resistant to amphotericin B were found to harbor mutations in ERG2, ERG3, ERG5, and ERG11, and were co-resistant to fluconazole [63,64,65,66].”
From Treatment of Invasive Candidiasis: A Narrative Review (2018) · cites this paper as [66]
Acquired resistance to amphotericin B is rare, and involves reduced ergosterol biosynthesis and the production of alternative sterols to which amphotericin B has low affinity.
“Acquired resistance is also rare, and involves reduced ergosterol biosynthesis and the production of alternative sterols to which amphotericin B has low affinity.”
From Treatment of Invasive Candidiasis: A Narrative Review (2018) · cites this paper as [66]
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- Authors
- Jensen, R. H., Astvad, K. M. T., Silva, L. V., Sanglard, D., Jørgensen, R., Nielsen, K. F., Mathiasen, E. G., Doroudian, G., Perlin, D. S., & Arendrup, M. C.
- Affiliations
- Statens Serum Institut (DK)
- Centre Hospitalier Universitaire Vaudois (CH)
- Technical University of Denmark (DK)
- Herlev Hospital (DK)
- Rutgers Health (US)
- Corresponding author
- Arendrup, Maiken Cavling
- ORCID
- Venue
- Journal of Antimicrobial Chemotherapy
- Publisher
- Oxford University Press (OUP)
- Published
- 2015-05-27
- Volume
- 70
- Issue
- 9
- Pages
- 2551-2555
- ISSN
- 0305-7453 (ISSN-L)
- 1460-2091
- PMC
- PMC4553713
- OpenAlex
- W1949381873
- Cited by
- 95
- References
- 28
- Citations by year
- 2026: 8 · 2025: 7 · 2024: 12 · 2023: 13 · 2022: 6 · 2021: 7 · 2020: 13 · 2019: 7 · 2018: 5 · 2017: 8 · 2016: 8 · 2015: 1
- FWCI
- 5.71
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Journal of Antimicrobial Chemotherapy (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- SERVAL (Université de Lausanne) (publishedVersion, other-oa)
- reroDoc Digital Library (submittedVersion)
- IRIS (submittedVersion)
- Funders
- Gilead (IX-DK-131-0286)
- European Society of Clinical Microbiology and Infectious Diseases (ESCMID)
- 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
- Candida albicans, multidrug resistance, azole resistance, echinocandin resistance, amphotericin B resistance, polyene resistance, ERG11 mutations, FKS1 mutations, sterol composition, antifungal susceptibility, virulence, Galleria mellonella
- MeSH terms
- Aged, Amphotericin B, Animals, Antifungal Agents, Azoles, Candida albicans, Candidiasis, DNA, Fungal, Genotype, Humans, Lepidoptera, Male, Microbial Sensitivity Tests, Mutation, Virulence, Survival Analysis, Sequence Analysis, DNA, Drug Resistance, Multiple, Fungal, Echinocandins, Multilocus Sequence Typing
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