Nonrandom Distribution of Azole Resistance across the Global Population of Aspergillus fumigatus.

The emergence of azole resistance in the pathogenic fungus has continued to increase, with the dominant resistance mechanisms, consisting of a 34-nucleotide tandem repeat (TR)/L98H and TR/Y121F/T289A, now showing a structured global distribution. Using hierarchical clustering and multivariate analysis of 4,049 isolates collected worldwide and genotyped at nine microsatellite loci using analysis of short tandem repeats of (STR), we show that can be subdivided into two broad clades and that alleles TR/L98H and TR/Y121F/T289A are unevenly distributed across these two populations. Diversity indices show that azole-resistant isolates are genetically depauperate compared to their wild-type counterparts, compatible with selective sweeps accompanying the selection of beneficial mutations. Strikingly, we found that azole-resistant clones with identical microsatellite profiles were globally distributed and sourced from both clinical and environmental locations, confirming that azole resistance is an international public health concern. Our work provides a framework for the analysis of isolates based on their microsatellite profile, which we have incorporated into a freely available, user-friendly R Shiny application (AfumID) that provides clinicians and researchers with a method for the fast, automated characterization of genetic relatedness. Our study highlights the effect that azole drug resistance is having on the genetic diversity of and emphasizes its global importance upon this medically important pathogenic fungus. Azole drug resistance in the human-pathogenic fungus continues to emerge, potentially leading to untreatable aspergillosis in immunosuppressed hosts. Two dominant, environmentally associated resistance mechanisms, which are thought to have evolved through selection by the agricultural application of azole fungicides, are now distributed globally. Understanding the effect that azole resistance is having on the genetic diversity and global population of will help mitigate drug-resistant aspergillosis and maintain the azole class of fungicides for future use in both medicine and crop protection.