Structure–Interaction Relationship of Polymyxins with Lung Surfactant

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（Multidrug-resistant Gram-negative bacteria）对全球公共卫生构成急迫且棘手的严峻威胁。多粘菌素（Polymyxins）已成为对抗这类“超级细菌”的最后一线治疗手段，但其针对肺部感染的抗菌疗效欠佳。本研究整合化学生物学与分子动力学模拟（molecular dynamics simulations）技术，系统探究了肺泡肺表面活性物质（alveolar lung surfactant）显著削弱多粘菌素抗菌活性的内在机制。研究发现，肺表面活性物质是一类基于磷脂的渗透屏障，可降低多粘菌素对靶标细菌的抗菌疗效。随后，我们阐明了多粘菌素与肺表面活性物质之间的结构-相互作用关联，并解析了调控多粘菌素穿透该关键表面活性层的热力学机制。此外，我们开发了一种新型类似物FADDI-235，无论在存在或缺失肺表面活性物质的条件下，该类似物均对革兰氏阴性菌表现出强效抗菌活性。本研究不仅为阐明肺表面活性物质对多粘菌素的隔离机制提供了全新视角，更为合理设计新一代脂肽类抗生素（lipopeptide antibiotics）以有效治疗革兰氏阴性菌肺炎（Gram-negative bacterial pneumonia）铺平了道路。