Genomic insights into multidrug-resistance, mating and virulence in Candida auris and related emerging species

Abstract

Candida auris is an emergent multidrug-resistant fungal pathogen causing increasing reports of outbreaks. While distantly related to C. albicans and C. glabrata, C. auris is closely related to rarely observed and often multidrug-resistant species from the C. haemulonii clade. Here, we analyze near complete genome assemblies for the four C. auris clades and three related species, and map intra- and inter-species rearrangements across the seven chromosomes. Using RNA-Seq-guided gene predictions, we find that most mating and meiosis genes are conserved and that clades contain either the MTLa or MTLα mating loci. Comparing the genomes of these emerging species to those of other Candida species identifies genes linked to drug resistance and virulence, including expanded families of transporters and lipases, as well as mutations and copy number variants in ERG11. Gene expression analysis identifies transporters and metabolic regulators specific to C. auris and those conserved with related species which may contribute to differences in drug response in this emerging fungal clade.

Ongoing Challenges with Healthcare-Associated Candida auris Outbreaks in Oman

“…The genome analysis of C. auris suggests that there are between 6500 and 8500 protein-coding sequences, including those for virulence factors such as biofilm formation and acquisition of drug resistance [41,42]. There is also widespread variation between geographic clades, with thousands of single nucleotide polymorphism (SNP) differences.…”

“…There is also widespread variation between geographic clades, with thousands of single nucleotide polymorphism (SNP) differences. At present, C. auris is separated into five geographic clades: The South Asian, African, South American, Iranian, and East Asian clades [8,39,41,43]. Phylogenomic analysis using ITS sequences and STR genotyping show that the Omani isolates belong to the South Asian clade.…”

Candida albicansgenetic background influences mean and heterogeneity of drug responses and genome stability during evolution to fluconazole

“…Furthermore, the frequency of aneuploidy among clinical isolates may be underestimated, as strain isolation methods (i.e., multiple growth cycles in rich medium) may impose a fitness cost that selects against aneuploid isolates. A mechanistic link between drug resistance and specific aneuploidies exists in multiple pathogenic fungal species (e.g., C. albicans, 22, 25-28 ; Cryptococcus neoformans , 29, 30 ; suggested in Candida auris, 31,32) . Because fluconazole tolerance and drug resistance are distinct and tolerance is sensitive to inhibitors that do not affect resistance (2,3) , it follows that antifungal tolerance likely evolves via a different subset of genes than resistance, although it is also possible that there is overlap between genes involved in tolerance and resistance.…”

The LUFS domain, its transcriptional regulator proteins, and drug resistance in the fungal pathogen Candida auris

“…Indeed, the mutation was not found in isolates outside of the clade, either in Colombia or elsewhere. It is not present in AmB‐resistant strains such as strain 6684 in India or B11220 in Japan, nor in AmB susceptible strains such as the reference strain B8441 from Pakistan ( and references therein).…”

“…In the case of Candida auris, we also performed an in silico analysis of raw sequencing reads from two RNA-Seq read sets of mature, spliced C. auris transcripts, from two different research groups, in order to check whether or not the predicted extended linker region of the conceptual database translations might be an artifact, that is, simply an intron that is never translated as part of the protein. Both of the RNA-seq data sets we searched 15,20 contained raw reads or read pairs and mRNA assemblies that were compatible with the existence of the linker extension in the protein, and contained none that would instead have been compatible with an intron hypothesis. Thus, although we cannot rule out that there may exist alternative splice forms (e.g., the GeneWise server at www.ebi.ac.uk/Tools/psa/genewise/ located an unlikely but possible intron splitting the protein sequence at … KNTLPQTARSFVCE -EHHLPRVALSMDAPQGFLF…), it appears that the whole linker region is translated in at least one splice variant.…”