scholarly journals Finding the needle in a haystack: Mapping antifungal drug resistance in fungal pathogen by genomic approaches

2019 ◽  
Vol 15 (1) ◽  
pp. e1007478 ◽  
Author(s):  
Dominique Sanglard
Keyword(s):  
Drug Resistance ◽  
Fungal Pathogen ◽  
Antifungal Drug ◽  
Antifungal Drug Resistance

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 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 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 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.

scholarly journals Mode of Selection and Experimental Evolution of Antifungal Drug Resistance in Saccharomyces cerevisiae

Genetics ◽  
2003 ◽  
Vol 163 (4) ◽  
pp. 1287-1298
Author(s):  
James B Anderson ◽  
Caroline Sirjusingh ◽  
Ainslie B Parsons ◽  
Charles Boone ◽  
Claire Wickens ◽  
...  
Keyword(s):  
Drug Resistance ◽  
Pleiotropic Effect ◽  
Antifungal Drug ◽  
Recessive Mutation ◽  
High Concentration ◽  
Gene Encoding ◽  
Antifungal Drug Resistance ◽  
Degree Of Dominance ◽  
A Genome ◽  
Abc Transporter Genes

Abstract We show that mode of selection, degree of dominance of mutations, and ploidy are determining factors in the evolution of resistance to the antifungal drug fluconazole in yeast. In experiment 1, yeast populations were subjected to a stepwise increase in fluconazole concentration over 400 generations. Under this regimen, two mutations in the same two chromosomal regions rose to high frequency in parallel in three replicate populations. These mutations were semidominant and additive in their effect on resistance. The first of these mutations mapped to PDR1 and resulted in the overexpression of the ABC transporter genes PDR5 and SNQ2. These mutations had an unexpected pleiotropic effect of reducing the residual ability of the wild type to reproduce at the highest concentrations of fluconazole. In experiment 2, yeast populations were subjected to a single high concentration of fluconazole. Under this regimen, a single recessive mutation appeared in each of three replicate populations. In a genome-wide screen of ∼4700 viable deletion strains, 13 were classified as resistant to fluconazole (ERG3, ERG6, YMR102C, YMR099C, YPL056C, ERG28, OSH1, SCS2, CKA2, SML1, YBR147W, YGR283C, and YLR407W). The mutations in experiment 2 all mapped to ERG3 and resulted in the overexpression of the gene encoding the drug target ERG11, but not PDR5 and SNQ2. Diploid hybrids from experiments 1 and 2 were less fit than the parents in the presence of fluconazole. In a variation of experiment 2, haploids showed a higher frequency of resistance than diploids, suggesting that degree of dominance and ploidy are important factors in the evolution of antifungal drug resistance.

scholarly journals Environmental Isolates of Azole-Resistant Aspergillus fumigatus in Germany

2015 ◽  
Vol 59 (7) ◽  
pp. 4356-4359 ◽  
Author(s):  
Oliver Bader ◽  
Jana Tünnermann ◽  
Anna Dudakova ◽  
Marut Tangwattanachuleeporn ◽  
Michael Weig ◽  
...  
Keyword(s):  
Drug Resistance ◽  
Aspergillus Fumigatus ◽  
Antifungal Drug ◽  
Clinical Samples ◽  
Environmental Isolates ◽  
Northern Germany ◽  
Content Type ◽  
Antifungal Drug Resistance ◽  
The World

ABSTRACTAzole antifungal drug resistance inAspergillus fumigatusis an emerging problem in several parts of the world. Here we investigated the distribution of such strains in soils from Germany. At a general positivity rate of 12%, most prevalently, we found strains with the TR34/L98H and TR46/Y121F/T289A alleles, dispersed along a corridor across northern Germany. Comparison of the distributions of resistance alleles and genotypes between environment and clinical samples suggests the presence of local clinical clusters.

scholarly journals Antifungal drug resistance: does it matter?

2002 ◽  
Vol 6 ◽  
pp. S47-S53 ◽  
Author(s):  
Thomas R. Rogers
Keyword(s):  
Drug Resistance ◽  
Antifungal Drug ◽  
Antifungal Drug Resistance

Antifungal drug resistance: Significance and mechanisms

2019 ◽  
pp. 63-86
Author(s):  
Sharvari Dharmaiah ◽  
Rania A. Sherif ◽  
Pranab K. Mukherjee
Keyword(s):  
Drug Resistance ◽  
Antifungal Drug ◽  
Antifungal Drug Resistance
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