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Evolution of antifungal-drug resistance: mechanisms and pathogen fitness

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Abstract

Like other microorganisms, fungi exist in populations that are adaptable. Under the selection imposed by antifungal drugs, drug-sensitive fungal pathogens frequently evolve resistance. Although the molecular mechanisms of resistance are well-characterized, there are few measurements of the impact of these mechanisms on pathogen fitness in different environments. To predict resistance before a new drug is prescribed in the clinic, the full spectrum of potential resistance mutations and the interactions among combinations of divergent mechanisms can be determined in evolution experiments. In the search for new strategies to manage drug resistance, measuring the limits of adaptation might reveal methods for trapping fungal pathogens in evolutionary dead ends.

Key Points

  • Like other microorganisms, fungi exist in populations that are adaptable. Under the selection imposed by antifungal drugs, initially drug-sensitive fungal pathogens frequently evolve resistance.

  • Although molecular mechanisms of resistance to antifungal drugs are well characterized, it is the evolutionary processes, the divergent mechanisms that arise by mutation and the impact on the fitness of the pathogen that determine the fate of resistance in fungal pathogen populations.

  • In fungi, unlike bacteria, drug-resistance (and other) genes do not usually spread horizontally among widely divergent taxa. The prevailing pattern is that antifungal-drug resistance evolves repeatedly in isolated populations.

  • The evidence for the evolution of resistance in real time comes from two different types of study: those that monitor fungal populations in patients undergoing antifungal drug therapy; and, in replicate, artificial cultures containing an antifungal drug.

  • A crucial factor in the evolution of resistance to drugs is whether different resistance mechanisms that occur in combination result in increased fitness in the presence of a drug, compared with the same mechanisms when they occur in isolation.

  • In the development of new antifungal drugs, the evolutionary potential for resistance can be predicted by subjecting known target genes to the Barlow–Hall procedure for mutagenic PCR and artificial recombination, and by allowing pathogen populations to evolve under artificial conditions designed to favour as many different mechanisms of resistance as possible.

  • Possible avenues for managing antifungal drug resistance in the future include developing methods to channel fungal evolution so that the pathogen population becomes more vulnerable to existing drugs, and interfering with the ability of the fungal population to produce phenotypic variation, which might be subject to natural selection and therefore impede evolvability.

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Acknowledgements

The author's research is supported by a Discovery Grant from the Natural Sciences and Engineering Research Council of Canada and an Operating Grant from the Canadian Institutes of Health Research.

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Competing interests

The author declares no competing financial interests.

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Glossary

RESISTANCE

The ability of a pathogen to continue to reproduce in the presence of an antifungal agent, here measured either as minimum inhibitory concentration or as fitness.

FITNESS

The extent to which an individual contributes genes to future generations, here measured as the number of generational doublings by a given fungal strain in a given environment in a set period of time or as an instantaneous rate of reproduction. In nature, ability to tolerate adverse environments, efficiency of sporulation and viability of offspring might also be important components of fitness.

TRAILING

The ability of a fungal strain to grow at drug concentrations above the minimum inhibitory concentration (MIC) in MIC tests.

TOLERANCE

The ability of the pathogen to survive while under inhibition by an agent.

PROPAGULE

Any fungal structure capable of dissemination and reproduction, including hyphal fragments, yeast cells or spores.

DIRECTIONAL SELECTION

Occurs when fitness increases with the phenotypic value of a trait, for example, the higher the resistance, the higher the rate of reproduction.

HYPHAL ANASTOMOSIS

A constitutive process in which the vegetative cells of filamentous fungi of the same, or closely related, species grow together and fuse with one another.

EVOLVABILITY

The capacity of an organism to express variation at the phenotypic level that might then be acted on by natural selection.

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Further reading

Figure 1: Chemical structures of some antifungal drugs and their targets.
Figure 2: Fitness landscapes for antifungal-drug-resistance mechanisms.