Dermatophytosis beyond Trichophyton indotineae: genomic characterization of rare keratinophilic fungi Myriodontium keratinophilum and Aphanoascus verrucosus in North India.

Fungal skin infections represent the fourth most prevalent disease globally, predominantly attributed to dermatophyte species such as Trichophyton. Nevertheless, sporadic instances of dermatophytosis may also arise from opportunistic, uncommon fungi. This study documents the association of keratinophilic fungi, Myriodontium keratinophilum and Aphanoascus verrucosus, with cases of dermatophytosis in Kashmir, North India. Internal transcribed spacer region sequencing of 64 isolates obtained from skin, hair, and nail samples of 62 patients identified 61% of isolates (n = 39) as M. keratinophilum, followed by Trichophyton indotineae and A. verrucosus in 20% (n = 13) and 19% (n = 12) cases, respectively. Furthermore, the first hybrid de novo genome assembly of M. keratinophilum is reported in the present study. Genomic analysis of both M. keratinophilum and A. verrucosus species revealed median intra-species single nucleotide polymorphism (SNP) differences of 100 and 27, respectively, suggesting highly related strains in the patient population. De novo functional annotation identified a higher number of coding regions in M. keratinophilum compared to T. indotineae and A. verrucosus, including carbohydrate-active enzymes (CAZymes) exhibiting unique substrate affinities and subtilisin 3 (SUB3) gene, previously implicated as a potential virulence gene in dermatophytes. Notably, in addition to all the multidrug transporters encoded by Trichophyton species, M. keratinophilum genome contains six putative ATP-binding cassette (ABC) transporters showing 40%-70% sequence similarity with the CDR1 gene. M. keratinophilum exhibited reduced susceptibility to multiple antifungals, including high minimum inhibitory concentrations (MICs) (>16 mg/L) against griseofulvin and itraconazole. Importantly, itraconazole is a primary therapeutic agent for terbinafine-resistant T. indotineae infections, underscoring the necessity for early and accurate identification and intervention of dermatophytic infections.IMPORTANCEThe study reports cases of dermatophytosis associated with two rare keratinophilic fungi, i.e., Myriodontium keratinophilum and Aphanoascus verrucosus. The cases mainly presented as tinea corporis and cruris, commonly caused by Trichophyton indotineae in the Indian subcontinent, which may remain undiagnosed due to a lack of molecular identification. Furthermore, the first-ever genome report of M. keratinophilum and its ab initio functional annotation is useful for further studies and management of opportunistic pathogens that exhibit reduced susceptibility towards itraconazole, the first-line drug of treatment for terbinafine-resistant T. indotineae infections. An early correct molecular identification of the etiologic agents of skin infections is warranted to tackle the new agents of dermatophytosis at the earliest stage.