scholarly journals Pathogenesis and Antifungal Drug Resistance of the Human Fungal Pathogen Candida glabrata

2011 ◽  
Vol 4 (1) ◽  
pp. 169-186 ◽  
Author(s):  
Michael Tscherner ◽  
Tobias Schwarzmüller ◽  
Karl Kuchler
Keyword(s):  
Drug Resistance ◽  
Fungal Pathogen ◽  
Candida Glabrata ◽  
Antifungal Drug ◽  
Antifungal Drug Resistance ◽  
Human Fungal Pathogen

scholarly journals The SUMO protease Ulp2 regulates genome stability and drug resistance in the human fungal pathogen Candida albicans

2021 ◽  
Author(s):  
Marzia Rizzo ◽  
Natthapon Soisangwan ◽  
Jan Soetaert ◽  
Samuel Vega-Estevez ◽  
Anna Selmecki ◽  
...  
Keyword(s):  
Drug Resistance ◽  
Candida Albicans ◽  
Fungal Pathogen ◽  
Genome Instability ◽  
Antifungal Drugs ◽  
Antifungal Drug ◽  
Genome Plasticity ◽  
Sumo Protease ◽  
Human Fungal Pathogen ◽  
Life Threatening

AbstractStress-induced genome instability in microbial organisms is emerging as a critical regulatory mechanism for driving rapid and reversible adaption to drastic environmental changes. In Candida albicans, a human fungal pathogen that causes life-threatening infections, genome plasticity confers increased virulence and antifungal drug resistance. Discovering the mechanisms regulating C. albicans genome plasticity is a priority to understand how this and other microbial pathogens establish life-threatening infections and develop resistance to antifungal drugs. We identified the SUMO protease Ulp2 as a critical regulator of C. albicans genome integrity through genetic screening. Deletion of ULP2 leads to hypersensitivity to genotoxic agents and increased genome instability. This increased genome diversity causes reduced fitness under standard laboratory growth conditions but enhances adaptation to stress, making ulp2Δ/Δ cells more likely to thrive in the presence of antifungal drugs. Whole-genome sequencing indicates that ulp2Δ/Δ cells counteract antifungal drug-induced stress by developing segmental aneuploidies of chromosome R and chromosome I. We demonstrate that intrachromosomal repetitive elements drive the formation of complex novel genotypes with adaptive power.

scholarly journals Tetraploidy accelerates adaption under drug-selection in a fungal pathogen

2021 ◽  
Author(s):  
Ognenka Avramovska ◽  
Emily Rego ◽  
Meleah A Hickman
Keyword(s):  
Drug Resistance ◽  
Genome Size ◽  
Fungal Pathogen ◽  
Fungal Pathogens ◽  
Antifungal Drug ◽  
Drug Selection ◽  
Antifungal Drug Resistance ◽  
Evolutionary Trajectories ◽  
Work Supports ◽  
Initial Genome

AbstractBaseline ploidy significantly impacts evolutionary trajectories, and in particular, tetraploidy has been associated with higher rates of adaptation compared to haploidy and diploidy. While the majority of experimental evolution studies investigating ploidy use Saccharomyces cerivisiae, the fungal pathogen Candida albicans is a powerful system to investigate ploidy dynamics, particularly in the context of antifungal drug resistance. C. albicans laboratory and clinical strains are predominantly diploid, but have also been isolated as haploid and polyploid. Here, we evolved diploid and tetraploid C. albicans for ∼60 days in the antifungal drug caspofungin. Tetraploid-evolved lines adapted faster than diploid-evolved lines and reached higher levels of caspofungin resistance. While diploid-evolved lines generally maintained their initial genome size, tetraploid-evolved lines rapidly underwent genome-size reductions and did so prior to caspofungin adaption. Furthermore, fitness costs in the absence of drug selection were significantly less in tetraploid-evolved lines compared to the diploid-evolved lines. Taken together, this work supports a model of adaptation in which the tetraploid state is transient but its ability to rapidly transition ploidy states improves adaptative outcomes and may drive drug resistance in fungal pathogens.

scholarly journals Candida glabrata Drug:H+Antiporter CgQdr2 Confers Imidazole Drug Resistance, Being Activated by Transcription Factor CgPdr1

2013 ◽  
Vol 57 (7) ◽  
pp. 3159-3167 ◽  
Author(s):  
Catarina Costa ◽  
Carla Pires ◽  
Tânia R. Cabrito ◽  
Adeline Renaudin ◽  
Michiyo Ohno ◽  
...  
Keyword(s):  
Drug Resistance ◽  
Transcription Factor ◽  
Multidrug Resistance ◽  
Candida Glabrata ◽  
Antifungal Drugs ◽  
Antifungal Drug ◽  
Major Facilitator Superfamily ◽  
Pathogenic Yeast ◽  
Content Type ◽  
Antifungal Drug Resistance

ABSTRACTThe widespread emergence of antifungal drug resistance poses a severe clinical problem. Though predicted to play a role in this phenomenon, the drug:H+antiporters (DHA) of the major facilitator superfamily have largely escaped characterization in pathogenic yeasts. This work describes the first DHA from the pathogenic yeastCandida glabratareported to be involved in antifungal drug resistance, theC. glabrata QDR2(CgQDR2) gene (ORFCAGL0G08624g). The expression ofCgQDR2inC. glabratawas found to confer resistance to the antifungal drugs miconazole, tioconazole, clotrimazole, and ketoconazole. By use of a green fluorescent protein (GFP) fusion, the CgQdr2 protein was found to be targeted to the plasma membrane inC. glabrata. In agreement with these observations,CgQDR2expression was found to decrease the intracellular accumulation of radiolabeled clotrimazole inC. glabrataand to play a role in the extrusion of this antifungal from preloaded cells. Interestingly, the functional heterologous expression ofCgQDR2in the model yeastSaccharomyces cerevisiaefurther confirmed the role of this gene as a multidrug resistance determinant: its expression was able to complement the susceptibility phenotype exhibited by itsS. cerevisiaehomologue,QDR2, in the presence of imidazoles and of the antimalarial and antiarrhythmic drug quinidine. In contrast to the findings reported for Qdr2, CgQdr2 expression does not contribute to the ability of yeast to grow under K+-limiting conditions. Interestingly,CgQDR2transcript levels were seen to be upregulated inC. glabratacells challenged with clotrimazole or quinidine. This upregulation was found to depend directly on the transcription factor CgPdr1, the major regulator of multidrug resistance in this pathogenic yeast, which has also been found to be a determinant of quinidine and clotrimazole resistance inC. glabrata.

scholarly journals Candida albicansgenetic background influences mean and heterogeneity of drug responses and genome stability during evolution to fluconazole

2018 ◽  
Author(s):  
Aleeza C. Gerstein ◽  
Judith Berman
Keyword(s):  
Drug Resistance ◽  
Candida Albicans ◽  
Genome Size ◽  
Fungal Pathogen ◽  
Genetic Background ◽  
Antifungal Drug ◽  
Human Fungal Pathogen ◽  
Evolutionary Level ◽  
Ancestral Strain ◽  
Strain Background

AbstractThe importance of within-species diversity in determining the evolutionary potential of a population to evolve drug resistance or tolerance is not well understood, including in eukaryotic pathogens. To examine the influence of genetic background, we evolved replicates of twenty different clinical isolates ofCandida albicans,a human fungal pathogen, in fluconazole, the commonly used antifungal drug. The isolates hailed from the majorC. albicansclades and had different initial levels of drug resistance and tolerance to the drug. The majority of replicates rapidly increased in fitness in the evolutionary environment, with the degree of improvement inversely correlated with ancestral strain fitness in the drug. Improvement was largely restricted to up to the evolutionary level of drug: only 4% of the evolved replicates increased resistance (MIC) above the evolutionary level of drug. Prevalent changes were altered levels of drug tolerance (slow growth of a subpopulation of cells at drug concentrations above the MIC) and increased diversity of genome size. The prevalence and predominant direction of these changes differed in a strain-specific manner but neither correlated directly with ancestral fitness or improvement in fitness. Rather, low ancestral strain fitness was correlated with high levels of heterogeneity in fitness, tolerance, and genome size among evolved replicates. Thus, ancestral strain background is an important determinant in mean improvement to the evolutionary environment as well as the diversity of evolved phenotypes, and the range of possible responses of a pathogen to an antimicrobial drug cannot be captured by in-depth study of a single strain background.ImportanceAntimicrobial resistance is an evolutionary phenomenon with clinical implications. We tested how replicates from diverse strains ofCandida albicans, a prevalent human fungal pathogen, evolve in the commonly-prescribed antifungal drug fluconazole. Replicates on average increased in fitness in the level of drug they were evolved to, with the least fit ancestral strains improving the most. Very few replicates increased resistance above the drug level they were evolved in. Notably, many replicates increased in genome size and changed in drug tolerance (a drug response where a subpopulation of cells grow slowly in high levels of drug) and variability among replicates in fitness, tolerance and genome size was higher in strains that initially were more sensitive to the drug. Genetic background influenced the average degree of adaptation and the evolved variability of many phenotypes, highlighting that different strains from the same species may respond and adapt very differently during adaptation.

scholarly journals Rampant transposition following RNAi loss causes hypermutation and antifungal drug resistance in clinical isolates of a human fungal pathogen

2021 ◽  
Author(s):  
Shelby Priest ◽  
Vikas Yadav ◽  
Cullen Roth ◽  
Tim Dahlmann ◽  
Ulrich Kueck ◽  
...  
Keyword(s):  
Drug Resistance ◽  
Nonsense Mutation ◽  
Fungal Pathogen ◽  
Genetic Locus ◽  
Antifungal Drugs ◽  
Antifungal Drug ◽  
Gene Encoding ◽  
Antifungal Drug Resistance ◽  
Trait Locus ◽  
Almost All

Abstract Microorganisms survive and compete within their environmental niches and avoid evolutionary stagnation by stochastically acquiring mutations that enhance fitness. Although increased mutation rates are often deleterious in multicellular organisms, hypermutation can be beneficial for microbes in the context of strong selective pressures. To explore how hypermutation arises in nature and elucidate its consequences, we employed a collection of 387 sequenced clinical and environmental isolates of Cryptococcus neoformans. This fungal pathogen is responsible for ~ 15% of annual AIDS-related deaths and is associated with high mortality rates, attributable to a dearth of antifungal drugs and increasing drug resistance. Isolates were screened for the ability to rapidly acquire antifungal drug resistance, and two robust hypermutators were identified. Insertion of the non-LTR Cnl1 retrotransposon was found to be responsible for the majority of drug-resistant isolates. Long-read whole-genome sequencing revealed both hypermutator genomes have two unique features: 1) hundreds of Cnl1 copies organized in subtelomeric arrays on both ends of almost all chromosomes, and 2) a nonsense mutation in the first exon of ZNF3, a gene encoding an RNAi component involved in silencing transposons. Quantitative trait locus mapping identified a significant genetic locus associated with hypermutation that includes the mutant znf3 allele, and CRISPR-mediated genome editing of the znf3 single-base pair nonsense mutation abolished the hypermutation phenotype and restored siRNA production. In sum, hypermutation and drug resistance in these isolates results from loss of RNAi combined with subsequent accumulation of a large genomic burden of a novel transposable element in C. neoformans.

scholarly journals Whole Genome Sequencing of Candida glabrata for Detection of Markers of Antifungal Drug Resistance

10.3791/56714 ◽  
2017 ◽  
Author(s):  
Chayanika Biswas ◽  
Sharon C-A. Chen ◽  
Catriona Halliday ◽  
Elena Martinez ◽  
Rebecca J. Rockett ◽  
...  
Keyword(s):  
Drug Resistance ◽  
Whole Genome Sequencing ◽  
Genome Sequencing ◽  
Candida Glabrata ◽  
Antifungal Drug ◽  
Whole Genome ◽  
Antifungal Drug Resistance

scholarly journals Rampant transposition following RNAi loss causes hypermutation and antifungal drug resistance in clinical isolates of a human fungal pathogen

2021 ◽  
Author(s):  
Shelby J Priest ◽  
Vikas Yadav ◽  
Cullen Roth ◽  
Tim Alexander Dahlmann ◽  
Ulrich Kuck ◽  
...  
Keyword(s):  
Drug Resistance ◽  
Nonsense Mutation ◽  
Fungal Pathogen ◽  
Genetic Locus ◽  
Antifungal Drugs ◽  
Antifungal Drug ◽  
Gene Encoding ◽  
Antifungal Drug Resistance ◽  
Trait Locus ◽  
Almost All

Microorganisms survive and compete within their environmental niches and avoid evolutionary stagnation by stochastically acquiring mutations that enhance fitness. Although increased mutation rates are often deleterious in multicellular organisms, hypermutation can be beneficial for microbes in the context of strong selective pressures. To explore how hypermutation arises in nature and elucidate its consequences, we employed a collection of 387 sequenced clinical and environmental isolates of Cryptococcus neoformans. This fungal pathogen is responsible for ~15% of annual AIDS-related deaths and is associated with high mortality rates, attributable to a dearth of antifungal drugs and increasing drug resistance. Isolates were screened for the ability to rapidly acquire antifungal drug resistance, and two robust hypermutators were identified. Insertion of the non-LTR Cnl1 retrotransposon was found to be responsible for the majority of drug-resistant isolates. Long-read whole-genome sequencing revealed both hypermutator genomes have two unique features: 1) hundreds of Cnl1 copies organized in subtelomeric arrays on both ends of almost all chromosomes, and 2) a nonsense mutation in the first exon of ZNF3, a gene encoding an RNAi component involved in silencing transposons. Quantitative trait locus mapping identified a significant genetic locus associated with hypermutation that includes the mutant znf3 allele, and CRISPR-mediated genome editing of the znf3 single-base pair nonsense mutation abolished the hypermutation phenotype and restored siRNA production. In sum, hypermutation and drug resistance in these isolates results from loss of RNAi combined with subsequent accumulation of a large genomic burden of a novel transposable element in C. neoformans.

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