Reducing the cost of resistance; experimental evolution in the filamentous fungus <i>Aspergillus nidulans</i>

Schoustra, Sijmen E.; Debets, A.J.M.; Slakhorst, M.; Hoekstra, Rolf F.

doi:10.1111/j.1420-9101.2006.01102.x

Cited by 58 publications

(74 citation statements)

References 47 publications

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“…Thus, it is expected that, in the absence of drug, the proportion of the population represented by the drug-resistant subpopulation will decrease or be eliminated from the population. Alternatively, further evolution in the absence of drug can give rise to compensatory mutations, resulting in improved fitness of drug-resistant mutants (4,17,20,30). In fungal cells, where resistance is acquired via changes in the genome rather than via horizontal gene transfer, the situation appears to be more complex.…”

Section: Discussionmentioning

confidence: 98%

Evolutionary Dynamics of Candida albicans during In Vitro Evolution

et al. 2011

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While mechanisms of resistance to major antifungal agents have been characterized in Candida albicans, little is known about the evolutionary trajectories during the emergence of drug resistance. Here, we examined the evolutionary dynamics of C. albicans that evolved in vitro in the presence or absence of fluconazole using the visualizing evolution in real-time (VERT) method, a novel experimental approach that facilitates the systematic isolation of adaptive mutants that arise in the population. We found an increase in the frequency of adaptive events in the presence of fluconazole compared to the no-drug controls. Analysis of the evolutionary dynamics revealed that mutations that led to increased drug resistance appeared frequently and that mutants with increased levels of resistance arose in independent lineages. Interestingly, most adaptive mutants with increased fitness in the presence of the drug did not exhibit a significant fitness decrease in the absence of the drug, supporting the idea that rapid resistance can arise from mutations in strains maintained in the population prior to exposure to the drug.The emergence of antimicrobial drug resistance in pathogens is a process of adaptive evolution, generally as a result of genetic mutations. Depending on the size of the population, the rate of mutation, and the relative fitness coefficients, the population may be heterogeneous, consisting of multiple resistant genotypes competing for expansion in a process called "clonal interference" (10, 12). Determining the evolutionary dynamics during adaptation is important for understanding the fundamental principles underlying how eukaryotic microbes evolve resistance to antimicrobial agents, a process that differs from that in bacteria because it is unlikely to involve horizontal gene transfer (1, 6).It is important to understand the frequencies with which adaptive mutants arise and expand, the evolutionary trajectories (the order of occurrence of adaptive mutations), and the potential convergence or divergence in the adaptive mechanisms between parallel populations in order to better appreciate how drug resistance can emerge in pathogens growing within the host. For example, knowledge of the frequency and order in which drug-resistant mutants arise in the population and whether the early-arising resistance mechanisms play a role in the level of drug resistance ultimately reached in the population can be used to predict the likely trajectory of a clinical infection and to develop appropriate therapeutic strategies.Candida albicans is the fourth most common cause of nosocomial infections, resulting in rates of mortality in U.S. hospitals that approach 50% (23,24,44). Emergence of resistance to almost all major antifungal agents used in treating C. albicans infections has been reported (15,22,29). Among the existing classes of antifungal drugs, azoles are the most commonly used, due to their low toxicity and their oral availability. The fact that they are fungistatic rather than fungicidal provides a clear opportunity...

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Section: Discussionmentioning

confidence: 98%

Evolutionary Dynamics of Candida albicans during In Vitro Evolution

et al. 2011

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“…Factors affecting the accumulation of compensatory mutations have been extensively studied in organisms with a rapid life cycle: bacteria, yeast and fungi. These studies identified factors including the rate of compensatory mutation (Poon and Chao, 2005;Gagneux et al, 2006;Schoustra et al, 2006), the environment (Bjö rkman et al, 2000;Reynolds, 2000) and the size of a population bottleneck (Levin et al, 2000;Maisnier-Patin et al, 2002). In organisms with longer generation time like weed species (often, only one generation per year), it is tempting to speculate that awaiting compensatory mutations might be less efficient than making use of the genetic diversity already present in the species.…”

Section: Discussionmentioning

confidence: 99%

The effects of the genetic background on herbicide resistance fitness cost and its associated dominance in Arabidopsis thaliana

et al. 2008

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The advantage of the resistance conferred by a mutation can sometimes be offset by a high fitness-cost penalty. This balance will affect possible fate of the resistance allele. Few studies have explored the impact of the genetic background on the expression of the resistance fitness cost and none has attempted to measure the variation in fitnesscost dominance. However, both the fitness penalty and its dominance may modify evolutionary trajectory and outcome. Here the impact of Arabidopsis thaliana intraspecific genetic diversity on fitness cost and its associated dominance was investigated by analysing 12 quantitative traits in crosses between a mutant conferring resistance to the herbicide 2,4-D and nine different natural genetic backgrounds. Fitness cost values were found to be more affected by intraspecific genetic diversity than fitness cost dominance, even though this effect depends on the quantitative trait measured. This observation has implications for the choice of the best strategy for preventing herbicide resistance development. In addition, our results pinpoint a potential compensatory improvement of the resistance fitness cost and its associated dominance by the genetic diversity locally present within a species.

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“…Especially for echinocandins, clinically resistant strains were isolated shortly after their launch (11,12). The strong adaptation ability of fungi is well documented (13)(14)(15)(16), so it was not surprising to see antifungal drug resistance emerging quickly. Mutation hot spots in FKS1, which encodes beta-glucan synthase, were detected in some of the resistant strains but not in all (10)(11)(12).…”

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confidence: 99%

“…Aspergillus nidulans is used as a model for adaptation studies (13,14). Vegetative nuclei in a colony are mitotically derived from a single spore nucleus, so the only source of genetic variation in an A. nidulans colony is somatic mutation, which then is clonally propagated as a mycelial sector (14).…”

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Using Aspergillus nidulans To Identify Antifungal Drug Resistance Mutations

Kaminskyj

2014

Eukaryot Cell

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Systemic fungal infections contribute to at least 10% of deaths in hospital settings. Most antifungal drugs target ergosterol (polyenes) or its biosynthetic pathway (azoles and allylamines), or beta-glucan synthesis (echinocandins). Antifungal drugs that target proteins are prone to the emergence of resistant strains. Identification of genes whose mutations lead to targeted resistance can provide new information on those pathways. We used Aspergillus nidulans as a model system to exploit its tractable sexual cycle and calcofluor white as a model antifungal agent to cross-reference our results with other studies. Within 2 weeks from inoculation on sublethal doses of calcofluor white, we isolated 24 A. nidulans adaptive strains from sectoring colonies. Meiotic analysis showed that these strains had single-gene mutations. In each case, the resistance was specific to calcofluor white, since there was no cross-resistance to caspofungin (echinocandin). Mutation sites were identified in two mutants by next-generation sequencing. These were confirmed by reengineering the mutation in a wild-type strain using a gene replacement strategy. One of these mutated genes was related to cell wall synthesis, and the other one was related to drug metabolism. Our strategy has wide application for many fungal species, for antifungal compounds used in agriculture as well as health care, and potentially during protracted drug therapy once drug resistance arises. We suggest that our strategy will be useful for keeping ahead in the drug resistance arms race.

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Reducing the cost of resistance; experimental evolution in the filamentous fungus Aspergillus nidulans

Cited by 58 publications

References 47 publications

Evolutionary Dynamics of Candida albicans during In Vitro Evolution

Evolutionary Dynamics of Candida albicans during In Vitro Evolution

The effects of the genetic background on herbicide resistance fitness cost and its associated dominance in Arabidopsis thaliana

Using Aspergillus nidulans To Identify Antifungal Drug Resistance Mutations

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