Department of Biochemistry and Molecular Biology, Drexel University College of Medicine, Philadelphia, PA 19102, USA.
Proc Natl Acad Sci U S A. 2013 Aug 27;110(35):14207-12. doi: 10.1073/pnas.1308268110. Epub 2013 Aug 12.
Bacitracin is a metalloantibiotic agent that is widely used as a medicine and feed additive. It interferes with bacterial cell-wall biosynthesis by binding undecaprenyl-pyrophosphate, a lipid carrier that serves as a critical intermediate in cell wall production. Despite bacitracin's broad use, the molecular details of its target recognition have not been elucidated. Here we report a crystal structure for the ternary complex of bacitracin A, zinc, and a geranyl-pyrophosphate ligand at a resolution of 1.1 Å. The antibiotic forms a compact structure that completely envelopes the ligand's pyrophosphate group, together with flanking zinc and sodium ions. The complex adopts a highly amphipathic conformation that offers clues to antibiotic function in the context of bacterial membranes. Bacitracin's efficient sequestration of its target represents a previously unseen mode for the recognition of lipid pyrophosphates, and suggests new directions for the design of next-generation antimicrobial agents.
杆菌肽是一种广泛用作药物和饲料添加剂的金属抗生素。它通过与十一碳烯焦磷酸结合来干扰细菌细胞壁的生物合成，十一碳烯焦磷酸是一种脂质载体，作为细胞壁生成的关键中间体。尽管杆菌肽的用途广泛，但它的靶标识别的分子细节尚未阐明。在这里，我们报告了杆菌肽 A、锌和香叶基焦磷酸配体三元复合物的晶体结构，分辨率为 1.1Å。该抗生素形成一个紧凑的结构，完全包围配体的焦磷酸基团，以及侧翼的锌和钠离子。该复合物采用高度两亲性构象，为抗生素在细菌膜中的功能提供了线索。杆菌肽对其靶标的有效螯合代表了一种以前未见的识别脂质焦磷酸盐的模式，并为设计下一代抗菌剂提供了新的方向。
