Efimova Svetlana S, Malykhina Anna I, Ostroumova Olga S
Laboratory of Membrane and Ion Channel Modeling, Institute of Cytology of Russian Academy of Sciences, Tikhoretsky 4, 194064 Saint Petersburg, Russia.
Membranes (Basel). 2023 Jul 14;13(7):670. doi: 10.3390/membranes13070670.
The macrolide polyene antibiotic amphotericin B (AmB), remains a valuable drug to treat systemic mycoses due to its wide antifungal activity and low probability of developing resistance. The high toxicity of AmB, expressed in nephropathy and hemolysis, could be partially resolved by lowering therapeutic AmB concentration while maintaining efficacy. This work discusses the possibility of using plant polyphenols and alkaloids to enhance the pore-forming and consequently antifungal activity of AmB. We demonstrated that phloretin, phlorizin, naringenin, taxifolin, quercetin, biochanin A, genistein, resveratrol, and quinine led to an increase in the integral AmB-induced transmembrane current in the bilayers composed of palmitoyloleoylphosphocholine and ergosterol, while catechin, colchicine, and dihydrocapsaicin did not practically change the AmB activity. Cardamonin, 4'-hydroxychalcone, licochalcone A, butein, curcumin, and piperine inhibited AmB-induced transmembrane current. Absorbance spectroscopy revealed no changes in AmB membrane concentration with phloretin addition. A possible explanation of the potentiation is related to the phytochemical-produced changes in the elastic membrane properties and the decrease in the energy of formation of the lipid mouth of AmB pores, which is partially confirmed by differential scanning microcalorimetry. The possibility of AmB interaction with cholesterol in the mammalian cell membranes instead of ergosterol in fungal membranes, determines its high toxicity. The replacement of ergosterol with cholesterol in the membrane lipid composition led to a complete loss or a significant decrease in the potentiating effects of tested phytochemicals, indicating low potential toxicity of these compounds and high therapeutic potential of their combinations with the antibiotic. The discovered combinations of AmB with plant molecules that enhance its pore-forming ability in ergosterol-enriched membranes, seem to be promising for further drug development in terms of the toxicity decrease and efficacy improvement.
大环内酯多烯抗生素两性霉素B（AmB）因其广泛的抗真菌活性和较低的耐药性发生概率，仍然是治疗系统性真菌病的一种重要药物。AmB的高毒性表现为肾病和溶血，可通过在维持疗效的同时降低治疗用AmB浓度来部分解决。这项工作探讨了使用植物多酚和生物碱来增强AmB的成孔能力从而提高其抗真菌活性的可能性。我们证明，根皮素、根皮苷、柚皮素、紫杉叶素、槲皮素、鹰嘴豆芽素A、染料木黄酮、白藜芦醇和奎宁可使由棕榈酰油酰磷脂酰胆碱和麦角固醇组成的双层膜中AmB诱导的跨膜电流增加，而儿茶素、秋水仙碱和二氢辣椒素实际上并未改变AmB的活性。小豆蔻明、4'-羟基查耳酮、光甘草查耳酮A、紫铆因、姜黄素和胡椒碱抑制AmB诱导的跨膜电流。吸收光谱显示添加根皮素后AmB的膜浓度没有变化。这种增强作用的一个可能解释与植物化学物质引起的弹性膜特性变化以及AmB孔脂质口形成能量的降低有关，差示扫描量热法部分证实了这一点。AmB与哺乳动物细胞膜中的胆固醇而非真菌细胞膜中的麦角固醇相互作用的可能性决定了其高毒性。膜脂质组成中用胆固醇替代麦角固醇导致测试植物化学物质的增强作用完全丧失或显著降低，表明这些化合物的潜在毒性较低以及它们与抗生素组合的治疗潜力较高。发现的AmB与植物分子的组合在富含麦角固醇的膜中增强了其成孔能力，从降低毒性和提高疗效方面来看，似乎对进一步的药物开发很有前景。
