Unveiling Genome Plasticity as a Mechanism of Non-Antifungal-Induced Antifungal Resistance in Cryptococcus neoformans DOI Creative Commons
Lijun Zheng, Yi Xu, Chen Wang

et al.

Research Square (Research Square), Journal Year: 2024, Volume and Issue: unknown

Published: June 20, 2024

Abstract Cryptococcus neoformans, designated as a "critical priority" pathogen by the World Health Organization, poses significant therapeutic challenges with only three drug classes currently available for cryptococcosis treatment. The emergence of antifungal resistance, compounded cross-resistance, further limits efficacy. Aneuploidy, known its potential to induce diverse traits, including remains poorly documented in C. neoformans. Utilizing tunicamycin, well-established ER stress inducer, we investigated impact on aneuploidy formation Our findings reveal that both mild and severe induced tunicamycin result These aneuploid strains exhibit karyotypes, select karyotypes conferring resistance or cross-resistance fluconazole 5-flucytosine. Additionally, these display instability, spontaneously losing extra chromosomes absence stress. Transcriptome analysis unveiled simultaneous upregulation multiple resistance-associated genes strains, highlighting genome plasticity neoformans major mechanism contributing non-antifungal-induced resistance.

Language: Английский

Beyond resistance: antifungal heteroresistance and antifungal tolerance in fungal pathogens DOI
Feng Yang, Judith Berman

Current Opinion in Microbiology, Journal Year: 2024, Volume and Issue: 78, P. 102439 - 102439

Published: Feb. 23, 2024

Language: Английский

Citations

13
The role of gene copy number variation in antimicrobial resistance in human fungal pathogens DOI Creative Commons

Alan R. Jay,

David Jordan, Aleeza C. Gerstein

et al.

npj Antimicrobials and Resistance, Journal Year: 2025, Volume and Issue: 3(1)

Published: Jan. 6, 2025

Faced with the burden of increasing resistance to antifungals in many fungal pathogens and constant emergence new drug-resistant strains, it is essential assess importance various mechanisms. Fungi have relatively plastic genomes can tolerate genomic copy number variation (CNV) caused by aneuploidy gene amplification or deletion. In cases, these changes lead adaptation stressful conditions, including those antifungal drugs. Here, we specifically examine contribution CNVs resistance. We undertook a thorough literature search, collecting reports CNV, classifying examples CNV-conferred into four main find that human pathogens, there little evidence plays major role compared other types mutations. discuss why might be underestimating their approaches being used study them.

Language: Английский

Citations

1
Rapid Evolution of Multidrug Resistance in a Candida lusitaniae Infection during Micafungin Monotherapy DOI Creative Commons
Nancy E. Scott, Serin Edwin Erayil, Susan E Kline

et al.

Antimicrobial Agents and Chemotherapy, Journal Year: 2023, Volume and Issue: 67(8)

Published: July 10, 2023

Candida (Clavispora) lusitaniae is a rare, emerging non-albicans species that can cause life-threatening invasive infections, spread within hospital settings, and rapidly acquire antifungal drug resistance, including multidrug resistance. The frequency spectrum of mutations causing resistance in C. are poorly understood. Analyses serial clinical isolates any uncommon often analyze limited number samples collected over months therapy with multiple classes, limiting the ability to understand relationships between classes specific mutations. Here, we performed comparative genomic phenotypic analysis 20 bloodstream daily from an individual patient treated micafungin monotherapy during single 11-day admission. We identified decreased susceptibility 4 days after initiation isolate increased cross-resistance fluconazole, despite no history azole this patient. Only 14 unique nucleotide polymorphisms (SNPs) were all samples, three different FKS1 alleles among ERG3 missense mutation found only both fluconazole. This first evidence occurred echinocandin associated classes. Overall, evolution rapid emerge treatment first-line therapy.

Language: Английский

Citations

18
Understanding fluconazole tolerance in Candida albicans: implications for effective treatment of candidiasis and combating invasive fungal infections DOI Creative Commons

Yanru Feng,

Hui Lu, Malcolm Whiteway

et al.

Journal of Global Antimicrobial Resistance, Journal Year: 2023, Volume and Issue: 35, P. 314 - 321

Published: Nov. 2, 2023

Fluconazole (FLC) tolerant phenotypes in Candida species contribute to persistent candidemia and the emergence of FLC resistance. Therefore, making fungicidal eliminating tolerance are important for treating invasive fungal diseases (IFDs) caused by species. However, mechanisms remain be fully explored. This review discusses high incidence importance successfully clearing candidiasis. We further define characterize C. albicans suggest that is a strategy response damage whose mechanism differs from identifies global factors affecting highlights significance cell membrane wall integrity tolerance, guiding approaches combat IFDs

Language: Английский

Citations

17
Single-cell detection of copy number changes reveals dynamic mechanisms of adaptation to antifungals in Candida albicans DOI
Xin Zhou, Audrey Hilk, Norma V. Solis

et al.

Nature Microbiology, Journal Year: 2024, Volume and Issue: unknown

Published: Sept. 3, 2024

Language: Английский

Citations

5
Distinguishing mutants that resist drugs via different mechanisms by examining fitness tradeoffs DOI Creative Commons
Kara Schmidlin,

Sam Apodaca,

Daphne Newell

et al.

eLife, Journal Year: 2024, Volume and Issue: 13

Published: Sept. 10, 2024

There is growing interest in designing multidrug therapies that leverage tradeoffs to combat resistance. Tradeoffs are common evolution and occur when, for example, resistance one drug results sensitivity another. Major questions remain about the extent which reliable, specifically, whether mutants provide a given all suffer similar tradeoffs. This question difficult because drug-resistant observed clinic, even those evolved controlled laboratory settings, often biased towards large fitness benefits. Thus, mutations (and mechanisms) may be more diverse than current data suggests. Here, we perform experiments utilizing lineage-tracking capture fuller spectrum of give yeast cells advantage fluconazole, antifungal drug. We then quantify each 774 across 12 environments, finding these group into classes with characteristically different Their unique imply affects through underlying mechanisms. Some groupings find surprising. For some resist single drugs do not their combination, while others do. And same gene have others. These findings, on hand, demonstrate difficulty relying consistent or intuitive when treatments. On other by demonstrating hundreds adaptive can reduced few groups characteristic tradeoffs, our findings yet empower strategies More generally speaking, grouping likely affect mechanisms, work guides efforts map phenotypic effects mutation.

Language: Английский

Citations

5
Aneuploidy Mediates Rapid Adaptation to a Subinhibitory Amount of Fluconazole in Candida albicans DOI Creative Commons
Liu-liu Sun, Hao Li, Tianhua Yan

et al.

Microbiology Spectrum, Journal Year: 2023, Volume and Issue: 11(2)

Published: Feb. 28, 2023

Genome instability is a hallmark of C. albicans . Aneuploidy usually causes fitness loss in the absence stress but confers better under particular conditions.

Language: Английский

Citations

11
Distinguishing mutants that resist drugs via different mechanisms by examining fitness tradeoffs DOI Creative Commons
Kara Schmidlin,

Sam Apodaca,

Daphne Newell

et al.

eLife, Journal Year: 2024, Volume and Issue: 13

Published: March 18, 2024

There is growing interest in designing multidrug therapies that leverage tradeoffs to combat resistance. Tradeoffs are common evolution and occur when, for example, resistance one drug results sensitivity another. Major questions remain about the extent which reliable, specifically, whether mutants provide a given all suffer similar tradeoffs. This question difficult because drug-resistant observed clinic, even those evolved controlled laboratory settings, often biased towards large fitness benefits. Thus, mutations (and mechanisms) may be more diverse than current data suggests. Here, we perform experiments utilizing lineage-tracking capture fuller spectrum of give yeast cells advantage fluconazole, antifungal drug. We then quantify each 774 across 12 environments, finding these group into classes with characteristically different Their unique imply affects through underlying mechanisms. Some groupings find surprising. For some resist single drugs do not their combination, while others do. And same gene have others. These findings, on hand, demonstrate difficulty relying consistent or intuitive when treatments. On other by demonstrating hundreds adaptive can reduced few groups characteristic tradeoffs, our findings yet empower strategies More generally speaking, grouping likely affect mechanisms, work guides efforts map phenotypic effects mutation.

Language: Английский

Citations

4
Approaches for identifying and measuring heteroresistance in azole-susceptible Candida isolates DOI Creative Commons
Cécile Gautier,

Eli Isael Maciel,

Iuliana V. Ene

et al.

Microbiology Spectrum, Journal Year: 2024, Volume and Issue: 12(4)

Published: April 2, 2024

ABSTRACT Heteroresistance to antifungal agents poses a significant challenge in the treatment of fungal infections. Currently, absence established methods for detecting and measuring heteroresistance impedes progress understanding this phenomenon pathogens. In response gap, we present comprehensive set new optimized designed detect quantify azole Candida albicans . Here, define two primary assays heteroresistance: population analysis profiling, based on growth solid medium, single-cell assays, liquid culture. We observe good correlations between measurements obtained with validating their utility studying heteroresistance. also highlight that disk diffusion could serve as an additional tool rapid detection These collectively provide versatile toolkit researchers seeking assess C. They critical step forward characterization heteroresistance, providing framework investigating diverse species context other agents. Ultimately, these advancements will enhance our ability effectively measure drug responses combat IMPORTANCE involves varying antimicrobial susceptibility within clonal population. This allows survival rare resistant subpopulations during treatment, significantly complicating effective management However, hampers human propose address gap yeast , encompassing assays. By robust correlated through both work broader applications across clinically relevant species. understand failure therapy.

Language: Английский

Citations

4
Step-wise evolution of azole resistance through copy number variation followed by KSR1 loss of heterozygosity in Candida albicans DOI Creative Commons
Pétra Vande Zande, Cécile Gautier,

Nora Kawar

et al.

PLoS Pathogens, Journal Year: 2024, Volume and Issue: 20(8), P. e1012497 - e1012497

Published: Aug. 30, 2024

Antimicrobial drug resistance poses a global health threat, requiring deeper understanding of the evolutionary processes that lead to its emergence in pathogens. Complex dynamics involve multiple mutations can result cooperative or competitive (clonal interference) effects. Candida albicans, major fungal pathogen, displays high rates copy number variation (CNV) and loss heterozygosity (LOH). CNV LOH events large numbers genes could synergize during adaptation. Understanding contributions antifungal adaptation is challenging, especially context whole-population genome sequencing. Here, we document sequential evolution fluconazole tolerance then C. albicans isolate involving an initial on chromosome 4, followed by R involves KSR1. Similar KSR1, which encodes reductase sphingolipid biosynthesis pathway, were also detected independently evolved resistant isolates. We dissect specific KSR1 codons affect tolerance. The combination 4 results >500-fold decrease azole susceptibility relative progenitor, illustrating compelling example rapid, yet step-wise, interplay between evolution.

Language: Английский

Citations

4