Clinical Characteristics and Genomic Analysis of a Trichophyton indotineae Strain Resistant to Terbinafine and Fluconazole Isolated in Italy

Background: Antifungal resistance is an expanding and increasingly significant issue representing a global threat for public health. In the last few years, different cases of dermatophytosis infections due to terbinafine-resistant Trichophyton mentagrophytes have been reported worldwide. In particular, T. mentagrophytes genotype VIII, proposed as T. indotineae, represents an emerging pathogen showing increasing spread worldwide that exhibits reduced susceptibility to different antifungal agents. Objectives: Here, we characterise the genome of a T. indotineae clinical strain (named PG11NEG-TBRES) resistant to terbinafine and fluconazole isolated in the northern part of Italy. Methods: Whole genome sequencing was performed with the Illumina MiSeq and Oxford Nanopore MinION systems, and hybrid genome assembly was executed with Unicycler. Phylogenomic and copy number analyses were performed by core genome SNPs analysis and coverage depth of mapping reads. Results: PG11NEG-TBRES belonged to the T. mentagrophytes genotype VIII (known as T. indotineae) and analysis of SQLE gene showed that the PG11NEG-TBRES strain harboured Leu393Ser. Phylogenomic analysis revealed that PG11NEG-TBRES was clonally related to fluconazole-resistant strains; deep genomic analysis showed the presence of different mutations within ERG4, MDR1 and MFS genes involved in ergosterol biosynthesis and the presence of five copies of tinCYP51b in comparison to susceptible isolates. Conclusions: Our work highlights the importance of genomic characterisation to define the mechanism related to antifungal resistance and to monitor the spread of emerging dermatophytosis infections.