Jiang Xukai, Patil Nitin A, Xu Yuwen, Wickremasinghe Hasini, Zhou Qi Tony, Zhou Fanfan, Thompson Philip E, Wang Lushan, Xiao Min, Roberts Kade D, Velkov Tony, Li Jian
National Glycoengineering Research Center, Shandong University, Qingdao 266237, China.
Biomedicine Discovery Institute, Infection Program and Department of Microbiology, Monash University, Melbourne 3800, Australia.
J Med Chem. 2023 Dec 14;66(23):16109-16119. doi: 10.1021/acs.jmedchem.3c01497. Epub 2023 Nov 29.
Multidrug-resistant Gram-negative bacteria present an urgent and formidable threat to the global public health. Polymyxins have emerged as a last-resort therapy against these 'superbugs'; however, their efficacy against pulmonary infection is poor. In this study, we integrated chemical biology and molecular dynamics simulations to examine how the alveolar lung surfactant significantly reduces polymyxin antibacterial activity. We discovered that lung surfactant is a phospholipid-based permeability barrier against polymyxins, compromising their efficacy against target bacteria. Next, we unraveled the structure-interaction relationship between polymyxins and lung surfactant, elucidating the thermodynamics that govern the penetration of polymyxins through this critical surfactant layer. Moreover, we developed a novel analog, FADDI-235, which exhibited potent activity against Gram-negative bacteria, both in the presence and absence of lung surfactant. These findings shed new light on the sequestration mechanism of lung surfactant on polymyxins and importantly pave the way for the rational design of new-generation lipopeptide antibiotics to effectively treat Gram-negative bacterial pneumonia.
多重耐药革兰氏阴性菌对全球公共卫生构成了紧迫而巨大的威胁。多粘菌素已成为对抗这些“超级细菌”的最后一道防线；然而，它们对肺部感染的疗效不佳。在本研究中，我们结合化学生物学和分子动力学模拟，以研究肺泡肺表面活性物质如何显著降低多粘菌素的抗菌活性。我们发现肺表面活性物质是一种基于磷脂的针对多粘菌素的渗透屏障，损害了它们对靶细菌的疗效。接下来，我们揭示了多粘菌素与肺表面活性物质之间的结构 - 相互作用关系，阐明了控制多粘菌素穿透这一关键表面活性物质层的热力学原理。此外，我们开发了一种新型类似物FADDI - 235，它在有和没有肺表面活性物质的情况下，对革兰氏阴性菌均表现出强效活性。这些发现为肺表面活性物质对多粘菌素的隔离机制提供了新的见解，并且重要的是为合理设计新一代脂肽抗生素以有效治疗革兰氏阴性菌肺炎铺平了道路。
