Compensatory expression of multidrug-resistance genes encoding ABC transporters in dermatophytes

Abstract

Genomic sequencing of several dermatophyte species has revealed that they show small differences in genetic content and genome organization, although each fungus has adapted to specific niches. Thus, it seemed relevant to compare gene expression between species. Here, we examined the transcription modulation of three ATP-binding cassette (ABC) transporter genes (pdr1, mdr2 and mdr4), which code for membrane transporter proteins in four species of Trichophyton; T. interdigitale, T. rubrum, T. tonsurans and T. equinum. These fungal species were challenged with sub-lethal doses of griseofulvin, itraconazole, terbinafine and amphotericin B. A mutant strain of T. interdigitale, Dmdr2, was also analysed for the modulation of pdr1 and mdr4 genes to evaluate the possible functional interaction among these three genes. Disruption of the mdr2 gene resulted in the accumulation of high levels of mdr4 transcripts when challenged with griseofulvin, suggesting that the mdr4 gene is compensating for the inactivation of mdr2 by providing resistance to this antifungal. Although the three ABC transporter genes have high homology between the four dermatophytes analysed, it is likely that they have specific functions, suggesting that the action of each drug is dependent on other factors inherent to each species. Our data suggest that these ABC transporter genes act synergistically in dermatophytes, and they may compensate for one another when challenged with antifungal drugs. This may be an important cause of therapeutic failure when treating fungal infections.

Terbinafine‐resistant strain of Trichophyton interdigitale strain isolated from a tinea pedis patient

“…Trichophyton rubrum isolated from human dermatophytosis was reported to exhibit TRF resistance . Resistance of dermatophytes to antifungal drugs frequently results from overexpression of genes encoding ATP‐binding cassette (ABC) transporter proteins, including the pleiotropic drug resistance ( PDR1 ) and multidrug resistance ( MDR2 and MDR4 ) genes .…”

“…Trichophyton rubrum isolated from human dermatophytosis was reported to exhibit TRF resistance . Resistance of dermatophytes to antifungal drugs frequently results from overexpression of genes encoding ATP‐binding cassette (ABC) transporter proteins, including the pleiotropic drug resistance ( PDR1 ) and multidrug resistance ( MDR2 and MDR4 ) genes . ABC (ATP‐binding cassette) transporters consist of transmembrane domains that act not only as transporters of fungal cell metabolites but also as exclusion for toxic substances from the cell .…”

“…Trichophyton interdigitale is an anthropophilic species that is frequently isolated from tinea unguium and tinea pedis throughout the world . Itraconazole (ITZ) and terbinafine (TRF) have been used in the treatment of these infections for more than 20 years.…”

“…Trichophyton interdigitale is an anthropophilic species that is frequently isolated from tinea unguium and tinea pedis throughout the world. 1,9 Itraconazole (ITZ) and terbinafine (TRF) have been used in the treatment of these infections for more than 20 years. Using sequential passage in the presence of ITZ and TRF, Hryncewicz-Gw o zd z et al 3 and Yamada et al 4 demonstrated in vitro selection of ITZ-or TRF-resistant Trichophyton rubrum.…”

Antifungal Therapy: New Advances in the Understanding and Treatment of Mycosis

“…Increased expression of the ABC transporters genes TruMDR1 and TruMDR2 from T. rubrum is observed in the presence of azoles (Cervelatti et al, 2006; Fachin et al, 2006). The use of efflux pumps by dermatophytes is also implicated in resistance to other antifungals, such as terbinafine, amphotericin B and griseofulvin (Cervelatti et al, 2006; Paião et al, 2007; Yu et al, 2007; Ghannoum, 2016; Martins et al, 2016). …”