Efimova Svetlana S, Tevyashova Anna N, Olsufyeva Evgenia N, Bykov Evgeny E, Ostroumova Olga S
Group of Ion Channel Modeling, Institute of Cytology of the Russian Academy of Sciences, St. Petersburg, Russia.
Laboratory of Chemical Transformation of Antibiotics, Gause Institute of New Antibiotics of the Russian Academy of Medical Sciences, Moscow, Russia.
PLoS One. 2017 Nov 29;12(11):e0188573. doi: 10.1371/journal.pone.0188573. eCollection 2017.
A series of amides of the antifungal antibiotic amphotericin B (AmB) and its conjugates with benzoxaboroles was tested to determine whether they form pores in lipid bilayers and to compare their channel characteristics. The tested derivatives produced pores of larger amplitude and shorter lifetime than those of the parent antibiotic. The pore conductance was related to changes in the partial charge of the hydrogens of the hydroxyl groups in the lactone ring that determined the anion coordination in the channel. Neutralization of one of the polar group charges in the AmB head during chemical modification produced a pronounced effect by diminishing the dwell time of the polyene channel compared to modification of both groups. In this study, compounds that had a modification of one carboxyl or amino group were less effective in initializing phase separation in POPC-membranes compared to derivatives that had modifications of both polar groups as well as the parent antibiotic. The effects were attributed to the restriction of the aggregation process by electrical repulsion between charged derivatives in contrast to neutral compounds. The significant correlation between the ability of derivatives to increase the permeability of model membranes-causing the appearance of single channels in lipid bilayers or inducing calcein leakage from unilamellar vesicles-and the minimal inhibitory concentration indicated that the antifungal effect of the conjugates was due to pore formation in the membranes of target cells.
对一系列抗真菌抗生素两性霉素B（AmB）及其与苯并硼唑的缀合物进行了测试，以确定它们是否在脂质双层中形成孔，并比较它们的通道特性。与母体抗生素相比，测试的衍生物产生的孔幅度更大、寿命更短。孔电导与内酯环中羟基氢的部分电荷变化有关，该变化决定了通道中的阴离子配位。与修饰两个基团相比，化学修饰过程中AmB头部一个极性基团电荷的中和通过减少多烯通道的停留时间产生了显著影响。在本研究中，与修饰了两个极性基团的衍生物以及母体抗生素相比，修饰了一个羧基或氨基的化合物在引发POPC膜相分离方面效果较差。这些影响归因于带电衍生物之间的电排斥对聚集过程的限制，这与中性化合物形成对比。衍生物增加模型膜通透性的能力（导致脂质双层中出现单通道或诱导钙黄绿素从单层囊泡泄漏）与最小抑菌浓度之间的显著相关性表明，缀合物的抗真菌作用是由于在靶细胞膜中形成孔所致。
