以病原菌信号肽酶Ⅰ为靶标的新型抗生素的研究进展

Novel inhibitors against the bacterial signal peptidase Ⅰ

目前日益严重的细菌耐药性,使得具有新作用机制的抗生素研发更显迫切。细菌信号肽酶Ⅰ是众多病原菌的必需蛋白,负责分泌蛋白信号肽序列的切除,广泛参与毒力因子分泌、密度传感分子的成熟以及调节细胞对β-内酰胺类抗生素的天然耐受等众多生理过程。近年来,信号肽酶Ⅰ三维结构的确定以及酶与抑制剂复合物的结构和相互作用机制的阐明,都为筛选抑制信号肽酶Ⅰ活性的新型抗生素提供了新的突破点。迄今为止,已发现了3种类型的信号肽酶Ⅰ抑制剂——信号肽衍生物、β-内酰胺和环脂肽阿龙霉素。本文重点总结了近年来信号肽酶Ⅰ抑制剂的结构、活性、构效关系等方面的研究进展。

New antibiotics with novel modes of action and structures are urgently needed to combat the emergence of multidrug-resistant bacteria. Bacterial signal peptidase Ⅰ （SPase Ⅰ） is an indispensable enzyme responsible for cleaving the signal peptide of preprotein to release the matured proteins. Increasing evidence suggests that SPase Ⅰ plays a crucial role in bacterial pathogenesis by regulating the excretion of a variety of virulent factors, maturation of quorum sensing factor and the intrinsic resistance against β-lactams. Recently, breakthrough has been achieved in the understanding of three-dimensional structure of SPase Ⅰ as well as the mechanism of enzyme-inhibitors interaction. Three families of inhibitors are identified, i.e. signal peptide derivatives, β-lactams and arylomycins. In this article, we summarize the recent advance in the study of structure, activity and structure-activity relationship of SPase Ⅰ inhibitors.