Short-term evolution and dispersal patterns of fluconazole-resistance in Candida auris clade III

Abstract

The rapid increase in infections caused by the emerging fungal pathogen Candida auris is of global concern, and understanding its expansion is a priority. The phylogenetic diversity of the yeast is clustered in five major clades, among which clade III is particularly relevant, as most of its strains exhibit resistance to fluconazole, reducing the therapeutic alternatives and provoking outbreaks that are difficult to control. In this study, we have investigated the phylogenetic structure of clade III by analyzing a global collection of 566 genomes. We have identified three subgroups within clade III, among which two are genetically most closely related. Moreover, we have estimated the evolutionary rate of clade III to be 2.25e-7 s/s/y (2.87 changes per year). We found that one of these subgroups shows intrinsic resistance to fluconazole and is responsible for the majority of cases within this clade globally. We inferred that this subgroup may have originated around December 2010 (95% High Probability Density (HPD): April 2010-June 2011), and since then it has spread across continents, generating multiple large outbreaks, each with a unique pattern of transmission and dissemination. These results highlight the remarkable ability of the pathogen to adapt to its environment and its rapid global spread, underscoring the urgent need to address this epidemiological challenge effectively.IMPORTANCEThe number of cases affected by Candida auris has increased worryingly worldwide. Among the currently recognized clades, clade III has the highest proportion of fluconazole-resistant cases and is spreading very rapidly, causing large nosocomial outbreaks across the globe. By analyzing complete fungal genomes from around the world, we have confirmed the origin of this clade and unraveled its dispersal patterns in the early 2010s. This finding provides knowledge that may be helpful to the public health authorities for the control of the disease.

Keywords: Candida auris; dispersion; fluconazole resistance; fungal pathogen; phylogenetic structure.

Fig 1

Phylogenetic structure of clade III of C. auris. Global phylogeny of clade III of C. auris (n = 566). The phylogeny was constructed from 2,152 SNPs. The color of the branches indicates the subgroup (referred to as the SG label) of each sample. The first ring (from inner to outer) indicates the isolate source (clinical or hospital-based environmental source), the second ring shows the country of origin of each isolate, the third ring indicates mutations related to fluconazole resistance, the fourth ring shows mutations related to micafungin resistance, and the last ring shows the year of the culture of each isolate. Blank spaces in resistance rings mean that the isolates harbor the wildtype allele. Bootstrap support values of the three subgroups and the main outbreak/clusters are displayed.

Fig 2

Dated phylogeny of C. auris clade III subgroups SG2 and SG3 (n = 380). The Bayesian-based tree was built from 1,071 SNPs. The inferred date (MM/YYYY) of the ancestral origin of SG3 and SG2&3, as well as that of the most recent common ancestor (MRCA) of the main clusters in this analysis are indicated at the corresponding nodes. Red bars indicate 95% HPD. Branch tip colors indicate the origin country of each sample analyzed. The first column indicates the outbreak or cluster that corresponds to each sample analyzed. The second column shows the city/state for samples with that information. The third column indicates mutations associated with fluconazole resistance (ERG11 allele), while the last column indicates mutations associated with micafungin (FKS1 allele). ND means “not detected.”

Fig 3

Pairwise genetic distances of C. auris clade III subgroups SG2 and SG3. (A) Genetic distances between isolates of each outbreak/cluster. (B) Genetic distances between samples are not described as an outbreak or cluster.