PDF(Pubmed)
Abstract：
Bacitracin is a macrocyclic peptide antibiotic that is widely used as a topical treatment for infections caused by gram-positive bacteria. Mechanistically, bacitracin targets bacteria by specifically binding to the phospholipid undecaprenyl pyrophosphate (C55PP), which plays a key role in the bacterial lipid II cycle. Recent crystallographic studies have shown that when bound to C55PP, bacitracin adopts a highly ordered amphipathic conformation. In doing so, all hydrophobic side chains align on one face of the bacitracin-C55PP complex, presumably interacting with the bacterial cell membrane. These insights led us to undertake structure-activity investigations into the individual contribution of the nonpolar amino acids found in bacitracin. To achieve this we designed, synthesized, and evaluated a series of bacitracin analogues, a number of which were found to exhibit significantly enhanced antibacterial activity against clinically relevant, drug-resistant pathogens. As for the natural product, these next-generation bacitracins were found to form stable complexes with C55PP. The structure-activity insights thus obtained serve to inform the design of C55PP-targeting antibiotics, a key and underexploited antibacterial strategy.
摘要：
杆菌肽是一种大环肽抗生素，广泛用作革兰氏阳性细菌引起的感染的局部治疗。机械上,杆菌肽通过特异性结合磷脂十一烯基焦磷酸盐（C55PP）来靶向细菌，在细菌脂质II循环中起关键作用。最近的晶体学研究表明，当与C55PP结合时，杆菌肽采用高度有序的两亲构象。在这样做的时候，所有疏水侧链在杆菌肽-C55PP复合物的一个面上对齐，可能与细菌细胞膜相互作用。这些见解使我们对杆菌肽中发现的非极性氨基酸的个体贡献进行结构活性研究。为了实现这一点，我们设计了，合成，并评估了一系列杆菌肽类似物，发现其中许多对临床相关的抗菌活性显着增强，耐药病原体。至于天然产物，发现这些下一代杆菌肽与C55PP形成稳定的复合物。由此获得的结构-活性见解有助于为C55PP靶向抗生素的设计提供信息，一个关键和未充分利用的抗菌策略。
