Decoding azole resistance mechanisms and pathogenicity in Aspergillus section Fumigati through genomic analysis

Aspergillus fumigatus is the primary causative agent of aspergillosis. Cryptic species may exhibit variable pathogenic potential and antifungal resistance and, particularly those within the section Fumigati, have significant clinical and environmental relevance. However, the genomic and proteomic bases underlying these differences remain poorly understood. This study presents a comparative analysis of 42 genomes (including five newly sequenced genomes), together with their corresponding predicted proteomes, from A. fumigatus , and from four cryptic species: A. lentulus , A. udagawae , A. felis and A. hiratsukae . Notably, these represent the only genomes currently available for these cryptic species, allowing us to integrate antifungal resistance mechanisms, and virulence factors across the full existing genomic landscape. We showed that A. fumigatus retains a highly conserved core proteome, whereas A. felis and A. lentulus exhibit greater genomic plasticity. Our preliminary findings suggest that azole resistance is primarily driven by species-specific point mutations, which are not shared across the section Fumigati . Secondary metabolism pathways are the main difference observed among section Fumigati , with variations in biosynthetic gene clusters and mycotoxin production. Our findings emphasize the evolutionary balance between genomic conservation and evolutionary divergence in A. fumigatus sensu lato, determining azole resistance and pathogenicity-associated fitness. • Comparative genomics uncovers azole resistance diversity in Fumigati species. • Species-specific point mutations drive azole resistance across Fumigati. • Distinct secondary metabolite clusters define cryptic species diversity. • Core proteome functional composition remains similar among species.