Drug Delivery System Excellence Center, Department of Pharmaceutical Technology, Faculty of Pharmaceutical Sciences, Prince of Songkla University, Hat Yai, Songkhla 90110, Thailand; Molecular Recognition Materials Research Unit, Department of Pharmaceutical Chemistry, Faculty of Pharmaceutical Sciences, Prince of Songkla University, Hat Yai, Songkhla 90110, Thailand.
Molecular Recognition Materials Research Unit, Department of Pharmaceutical Chemistry, Faculty of Pharmaceutical Sciences, Prince of Songkla University, Hat Yai, Songkhla 90110, Thailand.
Int J Pharm. 2020 May 15;581:119265. doi: 10.1016/j.ijpharm.2020.119265. Epub 2020 Mar 23.
We demonstrated binding interactions of polymyxin B (PMB), PMB formulations in the mole ratios of 1:2 and 1:3 of PMB:sodium deoxycholate sulfate (SDCS) and a commercial PMB formulation (CPMB) with lipopolysaccharides (LPS). The 1:2 PMB formulation (78.5-135.2 nM) exhibited a lower number of binding sites to the tested LPS compared to CPMB (112.6-140.9 nM) whereas 1:3 PMB formulation exhibited a higher number of binding sites (143.9-340.2 nM). Similarly, in the presence of LPS, the 1:2 PMB formulation (163.8-221.4 nm) exhibited smaller particle sizes compared to PMB, CPMB and 1:3 PMB formulation (248.8-603.5 nm). Molecular docking simulation suggested that the fatty acyl tails of LPS wrap together to produce a pseudo-globular structure of PMB-LPS complex, and among those 1:2 PMB formulation formed a more stable structure. The primary forces behind this complex are hydrogen bonds and salt bridges among the LPS, PMB, and SDCS. This study revealed that the PMB, CPMB, and PMB formulations inserted into the LPS micelles to disrupt the LPS membrane, whereas the SDCS may induce aggregation. The 1:2 PMB formulation also had higher bacterial uptake than other PMB formulations. The 1:2 PMB formulation neutralized the LPS micelles and was effective against Escherichia coli and Pseudomonas aeruginosa.
我们展示了多粘菌素 B（PMB）、PMB 与脱氧胆酸钠硫酸盐（SDCS）摩尔比为 1:2 和 1:3 的制剂以及一种商业 PMB 制剂（CPMB）与脂多糖（LPS）的结合相互作用。与 CPMB（112.6-140.9 nM）相比，1:2 PMB 制剂（78.5-135.2 nM）对测试 LPS 的结合位点数量较少，而 1:3 PMB 制剂则表现出更多的结合位点（143.9-340.2 nM）。同样，在 LPS 存在的情况下，与 PMB、CPMB 和 1:3 PMB 制剂（248.8-603.5 nm）相比，1:2 PMB 制剂（163.8-221.4 nm）表现出较小的颗粒尺寸。分子对接模拟表明，LPS 的脂肪酸酰基尾部缠绕在一起，产生 PMB-LPS 复合物的拟球状结构，其中 1:2 PMB 制剂形成更稳定的结构。这种复合物的主要作用力是 LPS、PMB 和 SDCS 之间的氢键和盐桥。本研究表明，PMB、CPMB 和 PMB 制剂插入 LPS 胶束中以破坏 LPS 膜，而 SDCS 可能诱导聚集。与其他 PMB 制剂相比，1:2 PMB 制剂的细菌摄取量也更高。1:2 PMB 制剂中和 LPS 胶束，对大肠杆菌和铜绿假单胞菌有效。
