Pyrithione (2-mercaptopyridine-N-oxide) is a metal binding modified pyridine, the antibacterial activity of which was described over 60 years ago. The formulation of zinc-pyrithione is commonly used in the topical treatment of certain dermatological conditions. However, the characterisation of the cellular uptake of pyrithione has not been elucidated, although an unsubstantiated assumption has persisted that pyrithione and/or its metal complexes undergo a passive diffusion through cell membranes. Here, we have profiled specific membrane transporters from an unbiased interrogation of 532 E. coli strains of knockouts of genes encoding membrane proteins from the Keio collection. Two membrane transporters, FepC and MetQ, seemed involved in the uptake of pyrithione and its cognate metal complexes with copper, iron, and zinc. Additionally, the phenotypes displayed by CopA and ZntA knockouts suggested that these two metal effluxers drive the extrusion from the bacterial cell of potentially toxic levels of copper, and perhaps zinc, which hyperaccumulate as a function of pyrithione. The involvement of these distinct membrane transporters contributes to the understanding of the mechanisms of action of pyrithione specifically and highlights, more generally, the important role that membrane transporters play in facilitating the uptake of drugs, including metal–drug compounds.

中文翻译：

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参与大肠杆菌中吡啶硫酮抗菌活性的膜转运蛋白

Pyrithione (2-mercaptopyridine-N-oxide) 是一种金属结合修饰的吡啶，其抗菌活性在 60 多年前已有描述。吡啶硫酮锌制剂常用于某些皮肤病的局部治疗。然而，尚未阐明细胞摄取吡啶硫酮的特征，尽管一直存在未经证实的假设，即吡啶硫酮和/或其金属配合物通过细胞膜被动扩散。在这里，我们从对 532 个大肠杆菌的无偏见询问中分析了特定的膜转运蛋白来自 Keio 收藏的编码膜蛋白的基因敲除菌株。两种膜转运蛋白 FepC 和 MetQ 似乎参与了吡啶硫酮及其与铜、铁和锌的同源金属络合物的摄取。此外，CopA 和 ZntA 敲除所显示的表型表明，这两种金属外排物促使细菌细胞排出具有潜在毒性水平的铜，也许还有锌，它们作为吡啶硫酮的功能而过度积累。这些不同的膜转运蛋白的参与有助于理解吡啶硫酮的具体作用机制，并且更普遍地强调了膜转运蛋白在促进药物（包括金属-药物化合物）吸收方面所起的重要作用。