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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。
The current increasingly serious bacterial resistance, making a new mechanism for the development of antibiotics even more urgent. Bacterial signal peptidase Ⅰ is required for many pathogens, is responsible for the excision of secretory protein signal peptide sequences, extensively involved in the secretion of virulence factors, the maturation of density-sensing molecules and the natural tolerance of cells to β-lactam antibiotics and many other Physiological process. In recent years, the determination of the three-dimensional structure of signal peptidase Ⅰ and the elucidation of the structure and interaction mechanism between the enzyme and inhibitor complexes have provided a new breakthrough point for screening novel antibiotics that inhibit signal peptidase Ⅰ activity. To date, three types of signal peptidase I inhibitors, signal peptide derivatives, [beta] -lactams and cycloaliphatic peptides, have been found. This review focuses on the recent progress in the structure, activity, structure-activity relationship of signal peptidase I inhibitors.