Experimental evolution of drug resistance in human fungal pathogens

Gerstein, Aleeza C.; Sethi, Parul

doi:10.1016/j.gde.2022.101965

Cited by 4 publications

(4 citation statements)

References 53 publications

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“…However, many of these SNVs encoded synonymous mutations, including a missense and synonymous SNV in RIM101 from lineage P75063-T 64 and SC5314-A 1 . The overall pattern is that polyploidy, aneuploidy, and segmental aneuploidy is likely a faster route to adapting to FLC in diploid C. albicans isolates and these karyotypic mutations are more likely to repeatedly arise and be selected independently in different lineages than rare adaptive point mutations, at least in the early stages of FLC exposure ( Yang, Todd, et al 2021 ; Gerstein and Sethi 2022 ).…”

Section: Resultsmentioning

confidence: 99%

“…Currently, it is thought that antifungal drug tolerance occurs via enhanced signaling of cellular stress response pathways including modulation of the calcium signaling pathway, nutrient detection, and HSP90 activation ( Cowen and Steinbach 2008 ; Rosenberg et al 2018 ; Murphy and Bicanic 2021 ). Drug-tolerant fungal cells are often present as a distinct subpopulation and can evolve independently of drug resistance, existing alongside drug-resistant or susceptible cells ( Gerstein and Sethi 2022 ). Tolerance in fungi seems to be a stable characteristic and isolates that evolve increased tolerance do not change in the prolonged absence of FLC ( Rosenberg et al 2018 ).…”

Section: Introductionmentioning

confidence: 99%

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Antifungal Drug Concentration Impacts the Spectrum of Adaptive Mutations in Candida albicans

Todd

Soisangwan

Peters

et al. 2023

Molecular Biology and Evolution

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Invasive fungal infections are a leading global cause of human mortality. Only three major classes of antifungal drugs are widely used, and resistance to all three classes can arise rapidly. The most widely prescribed antifungal drug, fluconazole, disseminates rapidly and reaches a wide range of concentrations throughout the body. The impact of drug concentration on the spectrum and effect of mutations acquired during adaptation is not known for any fungal pathogen, and how the specific level of a given stress influences the distribution of beneficial mutations has been poorly explored in general. We evolved 144 lineages from three genetically distinct clinical isolates of Candida albicans to four concentrations of fluconazole (0, 1, 8, and 64 μg/ml) and performed comprehensive phenotypic and genomic comparisons of ancestral and evolved populations. Adaptation to different fluconazole concentrations resulted in distinct adaptive trajectories. In general, lineages evolved to drug concentrations close to their MIC50 (the level of drug that reduces growth by 50% in the ancestor) tended to rapidly evolve an increased MIC50 and acquired distinct segmental aneuploidies and copy number variations. By contrast, lineages evolved to drug concentrations above their ancestral MIC50 tended to acquire a different suite of mutational changes and increased in drug tolerance (the ability of a subpopulation of cells to grow slowly above their MIC50). This is the first evidence that different concentrations of drug can select for different genotypic and phenotypic outcomes in vitro and may explain observed in vivo drug response variation.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Antifungal Drug Concentration Impacts the Spectrum of Adaptive Mutations in Candida albicans

Todd

Soisangwan

Peters

et al. 2023

Molecular Biology and Evolution

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“…In many published experiments, the end-point was deliberately chosen to be when an increased MIC 50 was achieved or included a final experimental step that only selected resistant isolates for further analysis. Few studies have provided a description of isolates that went extinct or those that did not increase in resistance (Gerstein and Sethi 2022). The second is a pervasive publication bias against null results.…”

Section: Discussionmentioning

confidence: 99%

Constraint on boric acid resistance and tolerance evolvability inCandida albicans

Syvolos,

Salama,

Gerstein

2024

Preprint

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Boric acid is a broad-spectrum antimicrobial used to treat vulvovaginal candidiasis when patients relapse on the primary azole drug fluconazole. Candida albicans is the most common cause of vulvovaginal candidiasis, colloquially referred to as a "vaginal yeast infection". Little is known about the propensity of C. albicans to develop BA resistance or tolerance (the ability of a subpopulation to grow slowly in high levels of drug). We evolved 96 replicates from eight genotypically diverse C. albicans strains to increasing BA concentrations to examine whether they would evolve BA resistance and/or tolerance. We found that many replicates went extinct quickly. Although some replicates were able to grow in much higher levels of BA than the ancestral strains, evolved populations isolated from the highest terminal BA levels surprisingly showed only modest growth improvements and only at low levels of BA. No large increases in resistance or tolerance were observed in the evolved replicates. Overall, our findings illustrate that there may be evolutionary constraints limiting the emergence of BA resistance and tolerance, which could explain why it remains an effective treatment for recurrent yeast infections.

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“…The acquisition and emergence of antifungal drug resistance can be explained as an evolutionary response to the selective pressure exerted by the drug. The likelihood of resistance emerging due to genetic changes is influenced by several factors, including the number and doubling rate of fungal cells exposed to the drug, the number of different pathways that confer resistance, and the fitness costs associated with each pathway [54]. It is important to note that antifungal drug resistance can originate either in the host or in the environment.…”

Section: Impact Of Fungal Antimicrobial Resistancementioning

confidence: 99%

Fungal Drug Response and Antimicrobial Resistance

Osset-Trénor,

Pascual-Ahuir,

Proft

2023

JoF

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Antifungal resistance is a growing concern as it poses a significant threat to public health. Fungal infections are a significant cause of morbidity and mortality, especially in immunocompromised individuals. The limited number of antifungal agents and the emergence of resistance have led to a critical need to understand the mechanisms of antifungal drug resistance. This review provides an overview of the importance of antifungal resistance, the classes of antifungal agents, and their mode of action. It highlights the molecular mechanisms of antifungal drug resistance, including alterations in drug modification, activation, and availability. In addition, the review discusses the response to drugs via the regulation of multidrug efflux systems and antifungal drug–target interactions. We emphasize the importance of understanding the molecular mechanisms of antifungal drug resistance to develop effective strategies to combat the emergence of resistance and highlight the need for continued research to identify new targets for antifungal drug development and explore alternative therapeutic options to overcome resistance. Overall, an understanding of antifungal drug resistance and its mechanisms will be indispensable for the field of antifungal drug development and clinical management of fungal infections.

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Experimental evolution of drug resistance in human fungal pathogens

Cited by 4 publications

References 53 publications

Antifungal Drug Concentration Impacts the Spectrum of Adaptive Mutations in Candida albicans

Antifungal Drug Concentration Impacts the Spectrum of Adaptive Mutations in Candida albicans

Constraint on boric acid resistance and tolerance evolvability inCandida albicans

Fungal Drug Response and Antimicrobial Resistance

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