Wood Thomas M, Slingerland Cornelis J, Martin Nathaniel I
Biological Chemistry Group, Institute of Biology Leiden, Leiden University, Sylviusweg 72, Leiden 2333 BE, The Netherlands.
Department of Chemical Biology & Drug Discovery, Utrecht Institute for Pharmaceutical Sciences, Utrecht University, Universiteitsweg 99, Utrecht 3584 CG, The Netherlands.
J Med Chem. 2021 Aug 12;64(15):10890-10899. doi: 10.1021/acs.jmedchem.1c00176. Epub 2021 Jul 20.
The continuing rise of antibiotic resistance, particularly among Gram-negative pathogens, threatens to undermine many aspects of modern medical practice. To address this threat, novel antibiotics that utilize unexploited bacterial targets are urgently needed. Over the past decade, a number of studies have highlighted the antibacterial potential of macrocyclic peptides that target Gram-negative outer membrane proteins (OMPs). Recently, it was reported that the antibacterial activities of OMP-targeting macrocyclic peptidomimetics of the antimicrobial peptide protegrin-1 are dramatically enhanced upon linking to polymyxin E nonapeptide (PMEN). In this study, we describe a convergent, chemoenzymatic route for the convenient preparation of such conjugates. Specifically, we investigated the use of both amide bond formation and azide-alkyne ligation for connecting an OMP-targeting macrocyclic peptide to a PMEN building block (obtained by enzymatic degradation of polymyxin E). The conjugates obtained via both approaches display potent antibacterial activity against a range of Gram-negative pathogens including multi-drug-resistant isolates.
抗生素耐药性的持续上升，尤其是在革兰氏阴性病原体中，有可能破坏现代医学实践的许多方面。为应对这一威胁，迫切需要利用未被开发的细菌靶点的新型抗生素。在过去十年中，多项研究突出了靶向革兰氏阴性外膜蛋白（OMPs）的大环肽的抗菌潜力。最近，有报道称，抗菌肽protegrin-1的靶向OMP的大环肽模拟物与多粘菌素E九肽（PMEN）连接后，其抗菌活性显著增强。在本研究中，我们描述了一种用于方便制备此类缀合物的汇聚式化学酶促路线。具体而言，我们研究了使用酰胺键形成和叠氮化物-炔烃连接反应，将靶向OMP的大环肽与一个PMEN结构单元（通过多粘菌素E的酶促降解获得）连接起来。通过这两种方法获得的缀合物对一系列革兰氏阴性病原体，包括多重耐药菌株，均显示出强大的抗菌活性。
