Genomic characterization of antifungal resistance patterns in Candida auris clade I: A large-scale analysis of 647 global genomes.

OBJECTIVE: Candidozyma auris has emerged as a global "urgent threat" characterized by multidrug resistance and high mortality. While six distinct lineages have been identified, Clade I (South Asian) is the primary driver of global nosocomial outbreaks and exhibits the most profound resistance profiles. This study aims to provide a high-resolution genomic characterization of Clade I, focusing on the consolidation of resistance mechanisms and virulence factors that support its global dominance. METHODS: We performed a comprehensive genomic analysis focusing on a cohort of 647 Clade I isolates, selected from a total of 662 global C. auris genomes available in public repositories. Using a standardized bioinformatic pipeline, we conducted core-genome single-nucleotide polymorphisms-based phylogenetic reconstruction, non-synonymous mutation profiling of key resistance genes (TAC1B, FKS1, ERG11/6/3), and functional mapping of virulence-related pathways (ALS4, secretable aspartyl proteases [SAP5], LIP1). The remaining isolates from Clades II to VI were utilized as comparative reference groups to identify clade-specific signatures. RESULTS: Analysis of the Clade I cohort (n=647; 97.73% of the total dataset) revealed a significant consolidation of resistance markers. The Y132F and K143R substitutions in ERG11 were near-ubiquitous, often co-occurring with specific TAC1B variants (A640V, V742A). Notably, 24.32% of the Clade I isolates demonstrated a highly synchronized "genomic armor," characterized by the simultaneous presence of TAC1B (A:YTDQ/A:GSVG), FKS1 (S:SL), and deletions in ERG6/ERG3. Virulence profiling showed high-frequency conservation of biofilm-associated (ALS4) and proteolytic (SAP5) genes, suggesting a synergistic evolution of resilience and pathogenicity. CONCLUSION: This study delineates the genomic landscape of C. auris Clade I, highlighting how the consolidation of multiple resistance and virulence markers contributes to its clinical success. The high frequency of multidrug-resistant genotypes within this lineage mandates a transition toward genome-led surveillance and personalized antifungal stewardship.