Teikyo University Institute of Medical Mycology, Tokyo, Japan.
Asia International Institute of Infectious Disease Control, Teikyo University, Tokyo, Japan.
Mycoses. 2021 Aug;64(8):936-946. doi: 10.1111/myc.13286. Epub 2021 Apr 25.
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.
We examined the potential of T rubrum to develop resistance to ITC by analysing the mechanism of ITC resistance in TIMM20092.
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.
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.
Our study highlights the possible role of the ABC transporter TruMDR2 in ITC resistance of T. rubrum.
在多个国家已经出现了对抗真菌药物敏感性降低的皮肤癣菌。一株特比萘芬耐药的红色毛癣菌（Trichophyton rubrum）菌株 TIMM20092 也表现出对伊曲康唑（ITC）和伏立康唑（VRC）的敏感性降低。发现该菌株中编码 ABC 家族多药转运蛋白的两个基因（TruMDR2 和 TruMDR3）的表达高度上调。在 TIMM20092 中缺失 TruMDR3 消除了其对 VRC 的耐药性，但仅略微降低了其对 ITC 的耐药性。
通过分析 TIMM20092 中 ITC 耐药的机制，研究红色毛癣菌对 ITC 产生耐药性的可能性。
通过基因替换在 TIMM20092 中缺失 TruMDR2，并从前一株 TIMM20092 中生成一个 TruMDR3 缺失突变体（∆TruMDR3）。成功获得了 TruMDR2 单缺失突变体（∆TruMDR2）和 TruMDR2/TruMDR3 双缺失突变体（∆TruMDR2/3）。
表明抑制 TruMDR2 可消除 TIMM20092 和 TruMDR3 缺失突变体对 ITC 的耐药性，强烈表明 TruMDR2 是 TIMM20092 中 ITC 耐药的主要贡献者。
本研究强调了 ABC 转运蛋白 TruMDR2 在红色毛癣菌 ITC 耐药中的可能作用。
