Hac-Wydro K, Dynarowicz-Latka P, Grzybowska J, Borowski E
Faculty of Chemistry, Jagiellonian University, Ingardena 3, 30-060 Kraków, Poland.
J Colloid Interface Sci. 2005 Jul 15;287(2):476-84. doi: 10.1016/j.jcis.2005.02.038.
N-(1-piperidinepropionyl)amphotericin B methyl ester (in short, PAME), a low-toxicity amphotericin B derivative, has been investigated in Langmuir monolayers at the air/water interface alone and in mixtures with cellular membrane sterols (a mammalian sterol, cholesterol, and a fungal sterol, ergosterol) and a model phospholipid (DPPC). The analysis of the strength of interaction between PAME and both sterols as well as DPPC was based, on surface pressure measurements and analysis of the isothermal compressibility (C(s)(-1)), the mean area per molecule (A(12)), the excess free energy of mixing (DeltaG(Exc)) and the total free energy of mixing (DeltaG(M)). It has been found that the interactions between PAME and sterols are attractive; however, their strength is significantly weaker for mixtures of PAME with cholesterol than with ergosterol. This casts light on the improved selectivity of PAME toward fungal cells. The strongest interactions, found for PAME/DPPC mixtures, proved an important role of DPPC in the mechanism of reduced toxicity of PAME as compared to amphotericin B. Due to stable complex formation between PAME and DPPC the antibiotic is immobilized with DPPC molecules, which reduces the concentration of free antibiotic, which is capable of interacting with membrane sterols.
N-(1-哌啶丙酰基)两性霉素B甲酯（简称为PAME）是一种低毒的两性霉素B衍生物，已在空气/水界面的Langmuir单分子层中单独进行研究，并与细胞膜甾醇（一种哺乳动物甾醇，胆固醇，以及一种真菌甾醇，麦角甾醇）和一种模型磷脂（二棕榈酰磷脂酰胆碱，DPPC）混合进行研究。基于表面压力测量以及对等温压缩性（C(s)(-1)）、每分子平均面积（A(12)）、混合过剩自由能（DeltaG(Exc)）和混合总自由能（DeltaG(M)）的分析，对PAME与两种甾醇以及DPPC之间的相互作用强度进行了分析。已发现PAME与甾醇之间的相互作用具有吸引力；然而，PAME与胆固醇的混合物的相互作用强度明显弱于与麦角甾醇的混合物。这揭示了PAME对真菌细胞具有更高的选择性。在PAME/DPPC混合物中发现的最强相互作用证明了DPPC在PAME与两性霉素B相比毒性降低的机制中起重要作用。由于PAME与DPPC之间形成稳定的复合物，抗生素与DPPC分子固定在一起，这降低了能够与膜甾醇相互作用的游离抗生素的浓度。
