The evolution of drug resistance in clinical isolates of Candida albicans

Candida albicans is both a member of the healthy human microbiome and a major pathogen in immunocompromised individuals. Infections are typically treated with azole inhibitors of ergosterol biosynthesis often leading to drug resistance. Studies in clinical isolates have implicated multiple mechanisms in resistance, but have focused on large-scale aberrations or candidate genes, and do not comprehensively chart the genetic basis of adaptation. Here, we leveraged next-generation sequencing to analyze 43 isolates from 11 oral candidiasis patients. We detected newly selected mutations, including single-nucleotide polymorphisms (SNPs), copy-number variations and loss-of-heterozygosity (LOH) events. LOH events were commonly associated with acquired resistance, and SNPs in 240 genes may be related to host adaptation. Conversely, most aneuploidies were transient and did not correlate with drug resistance. Our analysis also shows that isolates also varied in adherence, filamentation, and virulence. Our work reveals new molecular mechanisms underlying the evolution of drug resistance and host adaptation. DOI: http://dx.doi.org/10.7554/eLife.00662.001

• Publication year

  2015

• Venue

  eLife

• Publication date

  2015-02-03

• Fields of study

  Biology, Medicine

• Identifiers
  DOI 10.7554/eLife.00662PMID 25646566PMCID 4383195
• External record

  Open on Semantic Scholar

• Source metadata

  Semantic Scholar, PubMed

• No claims are published for this paper.

• No concepts are published for this paper.

• Gene copy-number alterations: a cost-benefit analysis.

  2013cited by this paper
• The ‘obligate diploid’ Candida albicans forms mating-competent haploids

  2013cited by this paper
• Evolution and impact of subclonal mutations in chronic lymphocytic leukemia.

  2013cited by this paper
• Dynamic Large-Scale Chromosomal Rearrangements Fuel Rapid Adaptation in Yeast Populations

  2013cited by this paper
• The role of Candida albicans AP-1 protein against host derived ROS in in vivo models of infection

  2013cited by this paper
• The APSES transcription factor Efg1 is a global regulator that controls morphogenesis and biofilm formation in Candida parapsilosis

  2013cited by this paper
• Chromosomal duplication is a transient evolutionary solution to stress

  2012cited by this paper
• Importance of the Candida albicans cell wall during commensalism and infection.

  2012cited by this paper
• A recently evolved transcriptional network controls biofilm development in Candida albicans.

  2012cited by this paper
• Evolution of the cancer genome

  2012cited by this paper
• Improved Gene Ontology Annotation for Biofilm Formation, Filamentous Growth, and Phenotypic Switching in Candida albicans

  2012cited by this paper
• Global Analysis of the Evolution and Mechanism of Echinocandin Resistance in Candida glabrata

  2012cited by this paper
• Evolution of the cancer genome.

  2012cited by this paper
• The stepwise acquisition of fluconazole resistance mutations causes a gradual loss of fitness in Candida albicans

  2012cited by this paper
• Clonal evolution in relapsed acute myeloid leukemia revealed by whole genome sequencing

  2011cited by this paper
• Stress Alters Rates and Types of Loss of Heterozygosity in Candida albicans

  2011cited by this paper
• The Candida genome database incorporates multiple Candida species: multispecies search and analysis tools with curated gene and protein information for Candida albicans and Candida glabrata

  2011cited by this paper
• Immunosensing during colonization by Candida albicans: does it take a village to colonize the intestine?

  2011cited by this paper
• Functional Dissection of a Candida albicans Zinc Cluster Transcription Factor, the Multidrug Resistance Regulator Mrr1

  2011influential reference
• Stress-Induced Loss of Heterozygosity in Candida: a Possible Missing Link in the Ability to Evolve

  2011cited by this paper
• Candida albicans, a major human fungal pathogen

  2011cited by this paper
• Integrative Genomics Viewer

  2011cited by this paper
• Trinity: reconstructing a full-length transcriptome without a genome from RNA-Seq data

  2011cited by this paper
• Aneuploidy confers quantitative proteome changes and phenotypic variation in budding yeast

  2010cited by this paper
• Identification of aneuploidy-tolerating mutations.

  2010cited by this paper
• The Genome Analysis Toolkit: a MapReduce framework for analyzing next-generation DNA sequencing data.

  2010influential reference
• Genomic Plasticity of the Human Fungal Pathogen Candida albicans

  2010cited by this paper
• Systematic screens of a Candida albicans homozygous deletion library decouple morphogenetic switching and pathogenicity

  2010cited by this paper
• Loss of Heterozygosity at an Unlinked Genomic Locus Is Responsible for the Phenotype of a Candida albicans sap4Δ sap5Δ sap6Δ Mutant

  2010cited by this paper
• Variable tandem repeats accelerate evolution of coding and regulatory sequences.

  2010cited by this paper
• Gene Ontology and the annotation of pathogen genomes: the case of Candida albicans.

  2009cited by this paper
• Evolution of pathogenicity and sexual reproduction in eight Candida genomes

  2009cited by this paper
• Stress-induced phenotypic switching in Candida albicans.

  2009cited by this paper
• A Pathogenesis Assay Using Saccharomycescerevisiae and Caenorhabditiselegans Reveals Novel Roles for Yeast AP-1, Yap1, and Host Dual Oxidase BLI-3 in Fungal Pathogenesis

  2009cited by this paper
• Evolution in Candida albicans Populations During a Single Passage Through a Mouse Host

  2009cited by this paper
• Acquisition of Aneuploidy Provides Increased Fitness during the Evolution of Antifungal Drug Resistance

  2009cited by this paper
• Mutations in the multi‐drug resistance regulator MRR1, followed by loss of heterozygosity, are the main cause of MDR1 overexpression in fluconazole‐resistant Candida albicans strains

  2008cited by this paper
• Discovering the secrets of the Candida albicans agglutinin-like sequence (ALS) gene family--a sticky pursuit.

  2008cited by this paper
• The impact of next-generation sequencing technology on genetics.

  2008cited by this paper
• An isochromosome confers drug resistance in vivo by amplification of two genes, ERG11 and TAC1

  2008cited by this paper
• The Parasexual Cycle in Candida albicans Provides an Alternative Pathway to Meiosis for the Formation of Recombinant Strains

  2008cited by this paper
• Correction for The Yak1 Kinase Is Involved in the Initiation and Maintenance of Hyphal Growth in Candida albicans

  2008cited by this paper
• The Repertoire and Dynamics of Evolutionary Adaptations to Controlled Nutrient-Limited Environments in Yeast

  2008cited by this paper
• cis-Acting Elements within the Candida albicans ERG11 Promoter Mediate the Azole Response through Transcription Factor Upc2p

  2007cited by this paper
• Mutation as a Stress Response and the Regulation of Evolvability

  2007cited by this paper
• In vivo transcript profiling of Candida albicans identifies a gene essential for interepithelial dissemination

  2007cited by this paper
• The Competitive Cost of Antibiotic Resistance in Mycobacterium tuberculosis

  2006cited by this paper
• GenePattern 2.0

  2006cited by this paper
• A Mutation in Tac1p, a Transcription Factor Regulating CDR1 and CDR2, Is Coupled With Loss of Heterozygosity at Chromosome 5 to Mediate Antifungal Resistance in Candida albicans

  2006cited by this paper
• Ploidy controls the success of mutators and nature of mutations during budding yeast evolution.

  2006cited by this paper
• Aneuploidy and Isochromosome Formation in Drug-Resistant Candida albicans

  2006cited by this paper
• Intragenic tandem repeats generate functional variability

  2005cited by this paper
• Candida albicans Zinc Cluster Protein Upc2p Confers Resistance to Antifungal Drugs and Is an Activator of Ergosterol Biosynthetic Genes

  2005cited by this paper
• Regulation of cell-surface genes and biofilm formation by the C. albicans transcription factor Bcr1p.

  2005cited by this paper
• Mating in Candida albicans and the search for a sexual cycle.

  2005cited by this paper
• Alternative Candida albicans lifestyles: growth on surfaces.

  2005cited by this paper
• A switch from high-fidelity to error-prone DNA double-strand break repair underlies stress-induced mutation.

  2005cited by this paper
• Hsp90 Potentiates the Rapid Evolution of New Traits: Drug Resistance in Diverse Fungi

  2005cited by this paper
• Demonstration of Loss of Heterozygosity by Single-Nucleotide Polymorphism Microarray Analysis and Alterations in Strain Morphology in Candida albicans Strains during Infection

  2005cited by this paper
• PAUP* [Phylogenetic Analysis Using Parsimony (and Other Methods)]

  2004cited by this paper
• Driving change: the evolution of alternative genetic codes.

  2004cited by this paper
• Metagenes and molecular pattern discovery using matrix factorization

  2004cited by this paper
• Genome-Wide Single-Nucleotide Polymorphism Map for Candida albicans

  2004cited by this paper
• Functional and Structural Diversity in the Als Protein Family of Candida albicans*

  2004cited by this paper
• MALDI-TOF mass spectrometry-based SNP genotyping.

  2003cited by this paper
• Attributable mortality of nosocomial candidemia, revisited.

  2003cited by this paper
• Haploinsufficiency‐based large‐scale forward genetic analysis of filamentous growth in the diploid human fungal pathogen C.albicans

  2003cited by this paper
• Far3 and Five Interacting Proteins Prevent Premature Recovery from Pheromone Arrest in the Budding Yeast Saccharomyces cerevisiae

  2003cited by this paper
• Candidemia in critically ill patients: difference of outcome between medical and surgical patients

  2003cited by this paper
• Genome‐wide identification of fungal GPI proteins

  2003cited by this paper
• Nosocomial bloodstream infections in pediatric patients in United States hospitals: epidemiology, clinical features and susceptibilities

  2003cited by this paper
• A prospective observational study of candidemia: epidemiology, therapy, and influences on mortality in hospitalized adult and pediatric patients.

  2003cited by this paper
• A randomized and blinded multicenter trial of high-dose fluconazole plus placebo versus fluconazole plus amphotericin B as therapy for candidemia and its consequences in nonneutropenic subjects.

  2003cited by this paper
• Genomic screen for vacuolar protein sorting genes in Saccharomyces cerevisiae.

  2002cited by this paper
• Resistance Mechanisms in Clinical Isolates of Candida albicans

  2002cited by this paper
• MALDI-TOF mass spectrometry-based SNP genotyping.

  2002cited by this paper
• Evolution of drug resistance in Candida albicans.

  2002cited by this paper
• Prevalence of Molecular Mechanisms of Resistance to Azole Antifungal Agents in Candida albicans Strains Displaying High-Level Fluconazole Resistance Isolated from Human Immunodeficiency Virus-Infected Patients

  2001cited by this paper
• Bakers' yeast, a model for fungal biofilm formation.

  2001cited by this paper
• Biofilm Formation by the Fungal PathogenCandida albicans: Development, Architecture, and Drug Resistance

  2001cited by this paper
• The cost of antibiotic resistance from a bacterial perspective.

  2000cited by this paper
• Contribution of mutations in the cytochrome P450 14alpha-demethylase (Erg11p, Cyp51p) to azole resistance in Candida albicans.

  1999cited by this paper
• Formation of Azole-Resistant Candida albicans by Mutation of Sterol 14-Demethylase P450

  1999cited by this paper
• A G1 Cyclin Is Necessary for Maintenance of Filamentous Growth in Candida albicans

  1999cited by this paper
• Hospital Specificity, Region Specificity, and Fluconazole Resistance of Candida albicans Bloodstream Isolates

  1998cited by this paper
• Candida albicans ALS3 and insights into the nature of the ALS gene family

  1998cited by this paper
• Nonfilamentous C. albicans mutants are avirulent.

  1997cited by this paper
• Increased mRNA levels of ERG16, CDR, and MDR1 correlate with increases in azole resistance in Candida albicans isolates from a patient infected with human immunodeficiency virus

  1997influential reference
• The presence of an R467K amino acid substitution and loss of allelic variation correlate with an azole-resistant lanosterol 14alpha demethylase in Candida albicans

  1997cited by this paper
• A randomized trial comparing fluconazole with amphotericin B for the treatment of candidemia in patients without neutropenia. Candidemia Study Group and the National Institute.

  1994cited by this paper
• Candida Colonization and Subsequent Infections in Critically III Surgical Patients

  1994cited by this paper
• A Randomized Trial Comparing Fluconazole with Amphotericin B for the Treatment of Candidemia in Patients without Neutropenia

  1994cited by this paper
• BIOINFORMATICS ORIGINAL PAPER

  year unknowninfluential reference

• Parasex generates highly recombinant progeny in Candida albicans with increased virulence

  2026cites this paper
• Experimental Evolution of Pathogenic Candida spp.: Insights into Adaptive Processes and Evolutionary Dynamics.

  2026cites this paper
• Dual inhibition of ERG11 and CDR2 in drug-resistant Candida albicans by Indian phytochemicals: a combined in silico–in vitro approach

  2026cites this paper
• Recurrent mutations in the stress regulator Cap1 reveal a trade-off between azole resistance and oxidative stress response in Candida albicans

  2026cites this paper
• Profound cell wall remodeling in Candida parapsilosis during systemic infection confers simultaneous tolerance to echinocandins and host immunity

  2026cites this paper
• In silico screening of IMPPAT-derived phytochemicals targeting ERG6 and drug resistance–associated proteins in drug-resistant Candida albicans: virtual screening and molecular dynamics using alphafold models

  2026cites this paper
• FungAMR: A comprehensive portrait of antimicrobial resistance mutations in fungi

  2025cites this paper
• Targeted loss of heterozygosity in Candida albicans using CRISPR-Cas9

  2025cites this paper
• Unravelling azole resistance in fungal pathogens: molecular mechanisms, diagnostic challenges, and therapeutic strategies

  2025cites this paper
• Strain background interacts with chromosome 7 aneuploidy to determine commensal and virulence phenotypes in Candida albicans

  2025cites this paper
• MAESTRO uncovers tandem paralog dynamics as a core driver of fungal stress adaptation

  2025cites this paper
• Heterogeneity of Candida bloodstream isolates in an academic medical center and affiliated hospitals

  2025cites this paper
• The role of gene copy number variation in antimicrobial resistance in human fungal pathogens

  2025cites this paper
• Candida glabrata replicating within macrophages experiences amino acid deprivation, DNA damage, and chromosome instability

  2025cites this paper
• The impact of phenotypic heterogeneity on fungal pathogenicity and drug resistance

  2025cites this paper
• Yeast Spectrum and antifungal susceptibility in a Hospital in Southwestern China: A retrospective Study (2020-2024).

  2025cites this paper
• Microbial heterogeneity-mediated treatment evasion and the potential for engineered live biotherapeutic products.

  2025cites this paper
• Phenotypic and genotypic differences between bloodstream and non-blood Candida krusei isolates: implications for invasiveness and antifungal susceptibility

  2025cites this paper
• Antifungal resistance: Emerging mechanisms and implications (Review)

  2025cites this paper
• Strain background interacts with chromosome 7 aneuploidy to determine commensal and virulence phenotypes in Candida albicans

  2025cites this paper
• Uncovering the role of mitochondrial genome in pathogenicity and drug resistance in pathogenic fungi

  2025cites this paper
• Aneuploidy confers a unique transcriptional and phenotypic profile to Candida albicans

  2025cites this paper
• Character Virulence Association Factors and Gene Mutation Mediating Multidrug Resistance Phenotypes in Candidozyma duobushaemulonii

  2025cites this paper
• Optimizing Antifungal Therapies for Candida Infections: Evidence, Resistance, and Emerging Approaches.

  2025cites this paper
• Genome structural plasticity and copy number dynamics shape adaptive evolution in a barley fungal pathogen

  2025cites this paper
• FungAMR: a comprehensive database for investigating fungal mutations associated with antimicrobial resistance

  2025cites this paper
• Aneuploidy, polyploidy, and loss of heterozygosity distinguish serial bloodstream isolates of Candida albicans

  2025cites this paper
• Polygenetic Determinants of Azole Resistance, Tolerance, and Heteroresistance in Candida albicans

  2025cites this paper
• Targeted loss of heterozygosity in Candida albicans using CRISPR-Cas9 reveals the functional impact of allelic variation

  2025cites this paper
• The dynamics of loss of heterozygosity events in genomes

  2025cites this paper
• Distinct properties of human pathogenic Candida species revealed by systematic comparative phenotypic screening of clinical isolates

  2025cites this paper
• Potential role of lysine acetylation in the stepwise adaptation of Candida albicans to fluconazole

  2025cites this paper
• Overcoming antifungal resistance in Candida albicans via RNA interference: a therapeutic perspective

  2025influential citation
• Adaptive evolution of Candida albicans through modulating TOR signaling

  2025cites this paper
• Lethal genes in plants

  2025cites this paper
• Candida albicans: Insights into the Biology and Experimental Innovations of a Commonly Isolated Human Fungal Pathogen.

  2025cites this paper
• Stress-driven emergence of heritable non-genetic drug resistance

  2024cites this paper
• Gamma irradiation green synthesis of (polyacrylamide/chitosan/silver nanoparticles) hydrogel nanocomposites and their using as antifungal against Candida albicans and anti-cancer modulator

  2024cites this paper
• Candida albicans Recovered From Persistent Candidemia Exhibits Enhanced Virulence Traits

  2024cites this paper
• Candida albicans isolates contain frequent heterozygous structural variants and transposable elements within genes and centromeres

  2024cites this paper
• Candidiasis in breast cancer: Tumor progression or not?

  2024cites this paper
• Most azole resistance mutations in the Candida albicans drug target confer cross-resistance without intrinsic fitness cost

  2024cites this paper
• Advanced genetic techniques in fungal pathogen research

  2024cites this paper
• Candida albicans natural diversity: a resource to dissect fungal commensalism and pathogenesis.

  2024cites this paper
• The fungicidal effectiveness of 2-Chloro-3-hydrazinylquinoxaline, a newly developed quinoxaline derivative, against Candida species

  2024cites this paper
• Candida albicans and Candida glabrata: global priority pathogens

  2024cites this paper
• Unveiling the roles of CaSDH8 in Candida albicans: Implications for virulence and azole resistance

  2024cites this paper
• Selection of ethanol tolerant strains of Candida albicans by repeated ethanol exposure results in strains with reduced susceptibility to fluconazole

  2024influential citation
• Step-wise evolution of azole resistance through copy number variation followed by KSR1 loss of heterozygosity in Candida albicans

  2024cites this paper
• Evolution and strain diversity advance exploration of Candida albicans biology

  2024cites this paper
• New approaches to tackle a rising problem: Large-scale methods to study antifungal resistance

  2024cites this paper
• Single-cell detection of copy number changes reveals dynamic mechanisms of adaptation to antifungals in Candida albicans

  2024cites this paper
• Approaches for identifying and measuring heteroresistance in azole-susceptible Candida isolates

  2024cites this paper
• Drivers of diversification in fungal pathogen populations

  2024cites this paper
• Niche-specific microevolution of Candida glabrata (Nakaseomyces glabrata) during an infection.

  2024cites this paper
• A chemically induced attenuated strain of Candida albicans generates robust protective immune responses and prevents systemic candidiasis development

  2024cites this paper
• Genome-Wide DNA Changes Acquired by Candida albicans Caspofungin-Adapted Mutants

  2023cites this paper
• Genomic epidemiology of human candidaemia isolates in a tertiary hospital

  2023cites this paper
• Candida parapsilosis sensu stricto Antifungal Resistance Mechanisms and Associated Epidemiology

  2023cites this paper
• Candida albicans selection for human commensalism results in substantial within-host diversity without decreasing fitness for invasive disease

  2023cites this paper
• The Dynamic Fungal Genome: Polyploidy, Aneuploidy and Copy Number Variation in Response to Stress

  2023influential citation
• Interkingdom interactions between Pseudomonas aeruginosa and Candida albicans affect clinical outcomes and antimicrobial responses.

  2023cites this paper
• Resistance to Fluconazole of Candida albicans in Vaginal Isolates: a 10-Year Study in a Clinical Referral Center

  2023cites this paper
• The Candida albicans reference strain SC5314 contains a rare, dominant allele of the transcription factor Rob1 that modulates biofilm formation and oral commensalism

  2023cites this paper
• Hybrid adaptation is hampered by Haldane’s sieve

  2023cites this paper
• Genome-Wide Identification of Variants Associated with Antifungal Drug Resistance.

  2023cites this paper
• Aneuploidy and gene dosage regulate filamentation and host colonization by Candida albicans

  2023cites this paper
• Genetic Diversity of Human Fungal Pathogens

  2023cites this paper
• Aneuploidy Mediates Rapid Adaptation to a Subinhibitory Amount of Fluconazole in Candida albicans

  2023cites this paper
• Antifungal Drug Concentration Impacts the Spectrum of Adaptive Mutations in Candida albicans

  2023influential citation
• Copy Number Variation and Allele Ratio Analysis in Candida albicans Using Whole Genome Sequencing Data.

  2023cites this paper
• Genotypic diversity and unrecognized antifungal resistance among populations of Candida glabrata from positive blood cultures

  2023cites this paper
• Pol32, an accessory subunit of DNA polymerase delta, plays an essential role in genome stability and pathogenesis of Candida albicans

  2023cites this paper
• The Microevolution of Antifungal Drug Resistance in Pathogenic Fungi

  2023cites this paper
• Loss of Heterozygosity and Its Importance in Evolution

  2023cites this paper
• Emergence of Antifungal Resistant Subclades in the Global Predominant Phylogenetic Population of Candida albicans

  2023cites this paper
• Genotypic diversity and unrecognized antifungal resistance among populations of Candida glabrata from positive blood cultures

  2023cites this paper
• The Candida albicans reference strain SC5314 contains a rare, dominant allele of the transcription factor Rob1 that modulates filamentation, biofilm formation, and oral commensalism

  2023cites this paper
• Study of Candida species in various clinical specimens at UCMS-TH, Bhairahawa, Nepal

  2023cites this paper
• Small molecules restore azole activity against drug-tolerant and drug-resistant Candida isolates

  2023cites this paper
• Selection of Ethanol Tolerant Strains of Candida albicans by Repeated Ethanol Exposure Results in Strains with Reduced Susceptibility to Fluconazole

  2023cites this paper
• Small molecule II-6s synergizes with fluconazole against Candida albicans.

  2023cites this paper
• Acquisition of cross-azole tolerance and aneuploidy in Candida albicans strains evolved to posaconazole

  2022cites this paper
• Late Pleistocene-dated divergence between South Hemisphere populations of the non-conventional yeast L. cidri.

  2022cites this paper
• Emergence and evolution of virulence in human pathogenic fungi.

  2022cites this paper
• Biofilm Alterations on the Stepwise Acquisition of Fluconazole-resistant Candida Albicans Isolates

  2022cites this paper
• Genome plasticity in Candida albicans: A cutting-edge strategy for evolution, adaptation, and survival.

  2022cites this paper
• yEvo: experimental evolution in high school classrooms selects for novel mutations that impact clotrimazole resistance in Saccharomyces cerevisiae

  2022cites this paper
• Stress combined with loss of the Candida albicans SUMO protease Ulp2 triggers selection of aneuploidy via a two-step process

  2022cites this paper
• The importance of antimicrobial resistance in medical mycology

  2022cites this paper
• Single nucleotide polymorphisms and chromosomal copy number variation may impact the Sporothrix brasiliensis antifungal susceptibility and sporotrichosis clinical outcomes.

  2022cites this paper
• Development and applications of a CRISPR activation system for facile genetic overexpression in Candida albicans

  2022influential citation
• Experimental and in-host evolution of triazole resistance in human pathogenic fungi

  2022influential citation
• Whole Genome Sequencing Shows Genetic Diversity, as Well as Clonal Complex and Gene Polymorphisms Associated with Fluconazole Non-Susceptible Isolates of Candida tropicalis

  2022cites this paper
• Vaccines against candidiasis: Status, challenges and emerging opportunity

  2022cites this paper
• Genomic Variation-Mediating Fluconazole Resistance in Yeast

  2022cites this paper
• Molecular investigations on Candida glabrata clinical isolates for pharmacological targeting

  2022cites this paper
• Evaluation of Inoculum Preparation for Etest and EUCAST Broth Dilution to Detect Anidulafungin Polyresistance in Candida glabrata

  2022cites this paper
• Candida albicans exhibits heterogeneous and adaptive cytoprotective responses to antifungal compounds

  2022cites this paper
• Sequencing of ca-int-l gene of Candida Spp. In infected urinary tract among Iraqi women

  2022cites this paper