Acquisition of Aneuploidy Provides Increased Fitness during the Evolution of Antifungal Drug Resistance

Anna M Selmecki,Leah E Cowen,James B Anderson,Keely Dulmage,Judith Berman,Hiten D Madhani

doi:10.1371/journal.pgen.1000705

Anna M Selmecki, Leah E Cowen + Show 4 more

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https://doi.org/10.1371/journal.pgen.1000705

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Journal: PLoS Genetics	Publication Date: Oct 30, 2009
Citations: 337	License type: CC BY 4.0

Affiliation: University of Minnesota, University of Toronto

Abstract

The evolution of drug resistance is an important process that affects clinical outcomes. Resistance to fluconazole, the most widely used antifungal, is often associated with acquired aneuploidy. Here we provide a longitudinal study of the prevalence and dynamics of gross chromosomal rearrangements, including aneuploidy, in the presence and absence of fluconazole during a well-controlled in vitro evolution experiment using Candida albicans, the most prevalent human fungal pathogen. While no aneuploidy was detected in any of the no-drug control populations, in all fluconazole-treated populations analyzed an isochromosome 5L [i(5L)] appeared soon after drug exposure. This isochromosome was associated with increased fitness in the presence of drug and, over time, became fixed in independent populations. In two separate cases, larger supernumerary chromosomes composed of i(5L) attached to an intact chromosome or chromosome fragment formed during exposure to the drug. Other aneuploidies, particularly trisomies of the smaller chromosomes (Chr3–7), appeared throughout the evolution experiment, and the accumulation of multiple aneuploid chromosomes per cell coincided with the highest resistance to fluconazole. Unlike the case in many other organisms, some isolates carrying i(5L) exhibited improved fitness in the presence, as well as in the absence, of fluconazole. The early appearance of aneuploidy is consistent with a model in which C. albicans becomes more permissive of chromosome rearrangements and segregation defects in the presence of fluconazole.

Highlights

Candida albicans is the most prevalent fungal pathogen of humans and is commonly treated with fluconazole because of its low toxicity, low cost and oral availability
We recently found that i(5L) was acquired twice, in two genetically distinct bloodstream isolates from an individual patient, and that its appearance correlated with increases in the fluconazole minimal inhibitory concentration (MIC) [20], indicating that active changes in chromosome copy number are an important mechanism for the evolution of antifungal resistance in the clinical setting
In this study we analyzed changes in genome organization and copy number that are recognized as important contributors to antifungal drug resistance

Summary

Introduction

Candida albicans is the most prevalent fungal pathogen of humans and is commonly treated with fluconazole because of its low toxicity, low cost and oral availability. The acquisition of drug resistance is an evolutionary process that occurs because antimicrobials rarely kill an entire population [1]. The survivors are subject to strong natural selection for resistant phenotypes in the presence of a drug. The increasing use of prolonged courses of fungistatic antifungal therapies increases the incidence of acquired antifungal drug resistance (reviewed in [2,3,4]). Fluconazole is especially prone to result in resistance as it is fungistatic, not fungicidal and the effective size of surviving populations is large. Resistant subpopulations appear to be maintained in the host, since previously treated patients have a higher incidence of resistance to subsequent fluconazole treatments [5]

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