Jiang Xukai, Zhang Shuo, Azad Mohammad A K, Roberts Kade D, Wan Lin, Gong Bin, Yang Kai, Yuan Bing, Uddin Hemayet, Li Jingliang, Thompson Philip E, Velkov Tony, Fu Jing, Wang Lushan, Li Jian
Biomedicine Discovery Institute, Infection & Immunity Program and Department of Microbiology, Monash University, Clayton, Melbourne, Victoria 3800, Australia.
Department of Mechanical and Aerospace Engineering, Monash University, Melbourne, Victoria 3800, Australia.
ACS Infect Dis. 2020 Aug 14;6(8):2110-2119. doi: 10.1021/acsinfecdis.0c00190. Epub 2020 Jul 17.
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 A, B, M 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 A 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.
耐多药革兰氏阴性菌对人类健康构成严重的全球威胁。多粘菌素越来越多地被用作患者的一线治疗药物，以治疗由这些危及生命的“超级细菌”引起的感染。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。在此，我们首次对四种天然存在的多粘菌素A、B、M和粘菌素A（多粘菌素核心结构的代表性结构变体）与人肾近端小管细胞膜之间的相互作用进行了全原子分子动力学模拟。所有多粘菌素均自发插入膜的疏水区域并保留在其中，尽管它们的插入能力各不相同。多粘菌素A以独特的折叠构象完全穿透膜的疏水区域，而其他三种多粘菌素仅将其脂肪酰基尾插入该区域。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位的立体化学调节了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。
