Multidrug-resistant Gram-negative bacteria are a serious global threat to human health. Polymyxins are increasingly used in patients as a last-line therapy to treat infections caused by these life-threatening ‘superbugs’. Unfortunately, polymyxin-induced nephrotoxicity is the major dose-limiting factor and understanding its mechanism is crucial for the development of novel, safer polymyxins. Here, we undertook the first all-atom molecular dynamics simulations of the interaction between four naturally occurring polymyxins A₁, B₁, M₁ and colistin A (representative structural variations of the polymyxin core structure) and the membrane of human kidney proximal tubular cells. All polymyxins inserted spontaneously into the hydrophobic region of the membrane where they were retained, although their insertion abilities varied. Polymyxin A₁ completely penetrated into the hydrophobic region of the membrane with a unique folded conformation, whereas the other three polymyxins only inserted their fatty acyl tails into this region. Furthermore, local membrane defects and increased water penetration were induced by each polymyxin, which may represent the initial stage of cellular membrane damage. Finally, the structure–interaction relationship of polymyxins was investigated based on atomic interactions at the cell membrane level. The hydrophobicity at positions 6/7 and stereochemistry at position 3 regulated the interactions of polymyxins with the cell membrane. Collectively, our results provide new mechanistic insights into polymyxin-induced nephrotoxicity at the atomic level and will facilitate the development of new-generation polymyxins.

中文翻译：

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多粘菌素与人肾近端小管细胞膜的结构相互作用关系。

多重耐药革兰氏阴性菌是对人类健康的严重全球威胁。多粘菌素越来越多地用于患者作为治疗由这些危及生命的“超级细菌”引起的感染的最后一线疗法。不幸的是，多粘菌素诱导的肾毒性是主要的剂量限制因素，了解其机制对于开发新型、更安全的多粘菌素至关重要。在这里，我们对四种天然存在的多粘菌素 A ₁、B ₁、M ₁之间的相互作用进行了首次全原子分子动力学模拟和粘菌素 A（多粘菌素核心结构的代表性结构变异）和人肾近端肾小管细胞的膜。尽管它们的插入能力各不相同，但所有多粘菌素都会自发地插入到膜的疏水区域中，在那里它们被保留下来。多粘菌素 A ₁以独特的折叠构象完全渗透到膜的疏水区域，而其他三种多粘菌素仅将其脂肪酰基尾部插入该区域。此外，每种多粘菌素都会诱导局部膜缺陷和水渗透增加，这可能代表细胞膜损伤的初始阶段。最后，基于细胞膜水平的原子相互作用研究了多粘菌素的结构相互作用关系。6/7 位的疏水性和 3 位的立体化学调节多粘菌素与细胞膜的相互作用。总的来说，我们的结果在原子水平上为多粘菌素诱导的肾毒性提供了新的机制见解，并将促进新一代多粘菌素的开发。