Blake Marea J, Page Eleanor F, Smith Madeline E, Calhoun Tessa R
University of Tennessee Knoxville TN USA
RSC Chem Biol. 2024 Jul 8;5(10):981-988. doi: 10.1039/d4cb00106k. eCollection 2024 Oct 2.
Miltefosine (MLT) is an alkylphosphocholine with clinical success as an anticancer and antiparasitic drug. Although the mechanism of action of MLT is highly debated, the interaction of MLT with the membrane, specifically lipid rafts of eukaryotes, is well-documented. Recent reports suggest MLT impacts the functional membrane microdomains in bacteria - regions of the membrane structurally and functionally similar to lipid rafts. There have been conflicting reports, however, as to whether MLT impacts the overall fluidity of cellular plasma membranes. Here, we apply steady-state fluorescence techniques, generalized polarization of laurdan and anisotropy of diphenylhexatriene, to discern how MLT impacts the global ordering and lipid packing of membranes. Additionally, we investigate how the transport of a range of small molecules is impacted by MLT for and by employing time-resolved second harmonic scattering. Overall, we observe MLT does not have an influence on the overall ordering and packing of membranes. Additionally, we show that the transport of small molecules across the membrane can be significantly altered by MLT - although this is not the case for all molecules studied. The results presented here illustrate the potential use of MLT as an adjuvant to assist in the delivery of drug molecules in bacteria.
米替福新（MLT）是一种烷基磷胆碱，作为一种抗癌和抗寄生虫药物在临床上取得了成功。尽管MLT的作用机制存在很大争议，但MLT与膜，特别是真核生物的脂筏的相互作用已有充分记录。最近的报告表明，MLT会影响细菌中的功能性膜微区——膜中在结构和功能上与脂筏相似的区域。然而，关于MLT是否会影响细胞质膜的整体流动性，存在相互矛盾的报道。在这里，我们应用稳态荧光技术，即劳丹的广义极化和二苯基己三烯的各向异性，来识别MLT如何影响膜的整体有序性和脂质堆积。此外，我们通过时间分辨二次谐波散射研究了一系列小分子的运输如何受到MLT的影响。总体而言，我们观察到MLT对膜的整体有序性和堆积没有影响。此外，我们表明，MLT可以显著改变小分子跨膜运输——尽管并非所有研究的分子都是如此。此处给出的结果说明了MLT作为辅助剂在协助细菌中药物分子递送方面的潜在用途。
