Tsuyoshi Yamada1,2, Takashi Yaguchi3, Takashi Tamura4, Christine Pich5, Karine Salamin5, Marc Feuermann6, Michel Monod5. 1. Teikyo University Institute of Medical Mycology, Tokyo, Japan. 2. Asia International Institute of Infectious Disease Control, Teikyo University, Tokyo, Japan. 3. Medical Mycology Research Center, Chiba University, Chiba, Japan. 4. General Medical Education and Research Center, Teikyo University, Tokyo, Japan. 5. Department of Dermatology, Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland. 6. Swiss-Prot group, SIB Swiss Institute of Bioinformatics, Geneva, Switzerland.
Abstract
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.
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.
Authors: Carlos H Lopes Rocha; Flaviane M Galvão Rocha; Tamires A Bitencourt; Maíra P Martins; Pablo R Sanches; Antonio Rossi; Nilce M Martinez-Rossi Journal: J Fungi (Basel) Date: 2022-08-03