Itraconazole resistance of Trichophyton rubrum mediated by the ABC transporter TruMDR2

Background Dermatophytes showing reduced sensitivity to antifungal agents have emerged in several countries. One terbinafine resistant strain of Trichophyton rubrum, TIMM20092, also showed reduced sensitivity to itraconazole (ITC) and voriconazole (VRC). The expression of two genes (TruMDR2 and TruM...

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Bibliographic Details
Published in:Mycoses 2021-08, Vol.64 (8), p.936-946
Main Authors: Yamada, Tsuyoshi, Yaguchi, Takashi, Tamura, Takashi, Pich, Christine, Salamin, Karine, Feuermann, Marc, Monod, Michel
Format: Article
Language:English
Subjects:
ABC transporter
ABC transporters
Antifungal agents
Antifungal Agents - pharmacology
Arthrodermataceae - drug effects
Arthrodermataceae - genetics
ATP Binding Cassette Transporter, Subfamily B - genetics
ATP Binding Cassette Transporter, Subfamily B - metabolism
ATP-Binding Cassette Sub-Family B Member 4
dermatophytes
Drug Resistance, Fungal - genetics
Gene deletion
Humans
Itraconazole
Itraconazole - pharmacology
itraconazole resistance
Microbial Sensitivity Tests
Mutants
Terbinafine
Trichophyton rubrum
TruMDR2
Voriconazole
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Summary:Background Dermatophytes showing reduced sensitivity to antifungal agents have emerged in several countries. One terbinafine resistant strain of Trichophyton rubrum, TIMM20092, also showed reduced sensitivity to itraconazole (ITC) and voriconazole (VRC). The expression of two genes (TruMDR2 and TruMDR3) encoding multidrug transporters of the ABC family was found to be highly up‐regulated in this strain. Deletion of TruMDR3 in TIMM20092 abolished its resistance to VRC but only slightly reduced its resistance to ITC. Objectives We examined the potential of T rubrum to develop resistance to ITC by analysing the mechanism of ITC resistance in TIMM20092. Methods The deletion of TruMDR2 by gene replacement was performed in TIMM20092 and one TruMDR3‐lacking mutant (∆TruMDR3) previously generated from TIMM20092. TruMDR2 single and TruMDR2/TruMDR3 double mutants (∆TruMDR2 and ∆TruMDR2/3) were successfully obtained, respectively. Results The suppression of TruMDR2 was shown to abolish resistance to ITC in TIMM20092 and the TruMDR3‐lacking mutant, strongly suggesting that TruMDR2 is a major contributor to ITC resistance in TIMM20092. Conclusions Our study highlights the possible role of the ABC transporter TruMDR2 in ITC resistance of T. rubrum.
ISSN:0933-7407
1439-0507
DOI:10.1111/myc.13286