ArticlePLoS pathogens2012
Global analysis of the evolution and mechanism of echinocandin resistance in Candida glabrata.
Article in PLoS pathogens, 2012. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 109 papers.
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Who cites it
109 citing papers in PubMed, 193 citations in OpenAlex.
- Immunological fitness of echinocandin-resistantVirulence · 2026Article
- Slt2 kinase of the cell wall integrity pathway is required for Fks2-specific echinocandin resistance inMicrobiology spectrum · 2026Article
- Experimental Evolution of PathogenicMicroorganisms · 2026Review
- Echinocandin tolerance and persistencemBio · 2026Article
- Yeast infections in sterile body fluids: species distribution, antifungal susceptibility, and cross-cutting risk factors for fungemia, sepsis, and mortality (2019-2023).Frontiers in microbiology · 2026Article
- Character Virulence Association Factors and Gene Mutation Mediating Multidrug Resistance Phenotypes in Candidozyma duobushaemulonii.Mycopathologia · 2025Article
- The Role of Drug Resistance in Candida Inflammation and Fitness.Microorganisms · 2025Article
- Tn-seq screens inmSphere · 2025Article
- Insight into the Mechanisms and Clinical Relevance of Antifungal Heteroresistance.Journal of fungi (Basel, Switzerland) · 2025Review
- Echinocandin Adaptation inJournal of fungi (Basel, Switzerland) · 2025Article
- Antifungal drug resistance in Candida glabrata: role of cellular signaling and gene regulatory networks.FEMS yeast research · 2025Review
- Drug analysis of a fatal case of bloodstream infection combined with urinary tract infection due to echinocandin-resistantIDCases · 2025Article
- CAF to the Rescue! Potential and Challenges of Combination Antifungal Therapy for Reducing Morbidity and Mortality in Hospitalized Patients With Serious Fungal Infections.Open forum infectious diseases · 2024Review
- Transposon-sequencing (Tn-seq) of the Candida glabrata reference strain CBS138 reveals epigenetic plasticity, structural variation, and intrinsic mechanisms of resistance to micafungin.G3 (Bethesda, Md.) · 2024Article
- Inferring fungal growth rates from optical density data.PLoS computational biology · 2024Article
- Article
- Genomic description of acquired fluconazole- and echinocandin-resistance in patients with serialJournal of clinical microbiology · 2024Article
- A multidimensional assessment of in-host fitness costs of drug resistance in the opportunistic fungal pathogen Candida glabrata.FEMS yeast research · 2024Article
- The rapid emergence of antifungal-resistant human-pathogenic fungi.Nature reviews. Microbiology · 2023Review
- Is theMicroorganisms · 2023Article
49 more citing papers are in PubMed but not listed here.
Corrections and comments
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Authors and funding
10 authors at 6 institutions in 2 countries.
Funding
Abstract
The evolution of drug resistance has a profound impact on human health. Candida glabrata is a leading human fungal pathogen that can rapidly evolve resistance to echinocandins, which target cell wall biosynthesis and are front-line therapeutics for Candida infections. Here, we provide the first global analysis of mutations accompanying the evolution of fungal drug resistance in a human host utilizing a series of C. glabrata isolates that evolved echinocandin resistance in a patient treated with the echinocandin caspofungin for recurring bloodstream candidemia. Whole genome sequencing identified a mutation in the drug target, FKS2, accompanying a major resistance increase, and 8 additional non-synonymous mutations. The FKS2-T1987C mutation was sufficient for echinocandin resistance, and associated with a fitness cost that was mitigated with further evolution, observed in vitro and in a murine model of systemic candidemia. A CDC6-A511G(K171E) mutation acquired before FKS2-T1987C(S663P), conferred a small resistance increase. Elevated dosage of CDC55, which acquired a C463T(P155S) mutation after FKS2-T1987C(S663P), ameliorated fitness. To discover strategies to abrogate echinocandin resistance, we focused on the molecular chaperone Hsp90 and downstream effector calcineurin. Genetic or pharmacological compromise of Hsp90 or calcineurin function reduced basal tolerance and resistance. Hsp90 and calcineurin were required for caspofungin-dependent FKS2 induction, providing a mechanism governing echinocandin resistance. A mitochondrial respiration-defective petite mutant in the series revealed that the petite phenotype does not confer echinocandin resistance, but renders strains refractory to synergy between echinocandins and Hsp90 or calcineurin inhibitors. The kidneys of mice infected with the petite mutant were sterile, while those infected with the HSP90-repressible strain had reduced fungal burden. We provide the first global view of mutations accompanying the evolution of fungal drug resistance in a human host, implicate the premier compensatory mutation mitigating the cost of echinocandin resistance, and suggest a new mechanism of echinocandin resistance with broad therapeutic potential.
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