Biological Chemistry Group, Institute of Biology, Leiden University, Leiden 2333 BE, The Netherlands.
Institute for Pharmaceutical Microbiology, University of Bonn, Bonn 53115, Germany.
Proc Natl Acad Sci U S A. 2024 Jul 16;121(29):e2315310121. doi: 10.1073/pnas.2315310121. Epub 2024 Jul 11.
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 (CPP), which plays a key role in the bacterial lipid II cycle. Recent crystallographic studies have shown that when bound to CPP, bacitracin adopts a highly ordered amphipathic conformation. In doing so, all hydrophobic side chains align on one face of the bacitracin-CPP 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 CPP. The structure-activity insights thus obtained serve to inform the design of CPP-targeting antibiotics, a key and underexploited antibacterial strategy.
杆菌肽是一种大环肽抗生素，广泛用作治疗革兰氏阳性菌引起的感染的局部治疗药物。从机制上讲，杆菌肽通过特异性结合磷脂十一异戊烯焦磷酸（CPP）来靶向细菌，CPP 在细菌脂质 II 循环中起着关键作用。最近的晶体学研究表明，当与 CPP 结合时，杆菌肽采用高度有序的两亲性构象。这样一来，所有疏水性侧链都在杆菌肽-CPP 复合物的一个面上对齐，推测与细菌细胞膜相互作用。这些见解促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。为了实现这一目标，我们设计、合成和评估了一系列杆菌肽类似物，其中一些被发现对临床相关的耐药病原体具有显著增强的抗菌活性。与天然产物一样，这些新一代杆菌肽与 CPP 形成稳定的复合物。因此，获得的结构活性见解可用于指导 CPP 靶向抗生素的设计，这是一种关键且未充分利用的抗菌策略。
