Evolution of antifungal-drug resistance: mechanisms and pathogen fitness

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.