An antifungal macrolide
Amphotericin B, a polyene antifungal antibiotic, has been produced from a strain of Streptomyces nodosus with an IC50 of 0.028–0.290 μg/ml.
In vitro: Amphotericin B was the most effective drug for treating many life-threatening fungal infections. In cells expressing TLR2 and CD14, amphotericin B induced signal transduction and inflammatory cytokine release. In primary murine macrophages and human cell lines expressing TLR2, CD14, and the adapter protein MyD88, amphotericin induced NF-κB-dependent reporter activity and cytokine release, whereas cells deficient in any of these failed to respond. Cells with TLR4 mutation were less responsive to amphotericin B stimulation than cells expressing normal TLR4 [1]. Amphotericin B could interact with cholesterol, the major sterol of mammal membranes, thus limiting the usefulness of Amphotericin B due to its relatively high toxicity [2]. Low AmB concentrations (≤ 0.1 μM) induced a polarization potential in KCl-loaded liposomes suspended in an iso-osmotic sucrose solution, indicating K+ leakage. AmB (＞ 0.1 μM) allowed cations and anions movements. LPs suspended in an iso-osmotic NaCl solution and exposed to AmB (0.05 μM) exhibited a nearly total collapse of the negative membrane potential, indicated that Na+ entered into the cells [3].
In vivo: Amphotericin B prolonged the incubation time and decreased PrPSc accumulation in the hamster scrapie model. Amphotericin B markedly resulted in reduction of PrPSc levels in mice with transmissible subacute spongiform encephalopathies (TSSE) [4].
两性霉素B是一种多烯类抗真菌抗生素，由结节链霉菌菌株产生，其IC50为0.028–0.290μg/ml。
体外：两性霉素B是治疗许多危及生命的真菌感染最有效的药物。在表达TLR2和CD14的细胞中，两性霉素B诱导信号转导和炎性细胞因子释放。在表达TLR2、CD14和衔接蛋白MyD88的原代鼠巨噬细胞和人细胞系中，两性霉素诱导NF-κB依赖性报告基因活性和细胞因子释放，而缺乏任何这些的细胞都没有反应。与表达正常TLR4的细胞相比，具有TLR4突变的细胞对两性霉素B刺激的反应较弱[1]。两性霉素B可能与哺乳动物膜的主要固醇胆固醇相互作用，因此由于其相对较高的毒性而限制了两性霉素的用途[2]。
低AmB浓度（≤0.1μM）在悬浮于等渗蔗糖溶液中的KCl负载脂质体中诱导极化电位，表明K+渗漏。AmB（＞0.1μM）允许阳离子和阴离子运动。悬浮在等渗NaCl溶液中并暴露于AmB（0.05μM）的LPs表现出负膜电位几乎完全崩溃，表明Na+进入细胞[3]。
体内：两性霉素B延长了仓鼠瘙痒模型中的孵育时间并减少了PrPSc的积累。两性霉素B可显著降低传播性亚急性海绵状脑病（TSSE）小鼠的PrPSc水平[4]。
参考文献:
[1].?Sau K1,Mambula SS,Latz E,Henneke P,Golenbock DT,Levitz SM.The antifungal drug amphotericin B promotes inflammatory cytokine release by a Toll-like receptor- and CD14-dependent mechanism.J Biol Chem.2003 Sep 26;278(39):37561-8. Epub 2003 Jul 14.
[2].?Barwicz J1,Tancrède P.The effect of aggregation state of amphotericin-B on its interactions with cholesterol- or ergosterol-containing phosphatidylcholine monolayers.Chem Phys Lipids.1997 Feb 28;85(2):145-55.
[3].?Ramos H1,Valdivieso E,Gamargo M,Dagger F,Cohen BE.Amphotericin B kills unicellular leishmanias by forming aqueous pores permeable to small cations and anions.J Membr Biol.1996 Jul;152(1):65-75.
[4].?Demaimay R1,Adjou K,Lasmézas C,Lazarini F,Cherifi K,Seman M,Deslys JP,Dormont D.Pharmacological studies of a new derivative of amphotericin B, MS-8209, in mouse and hamster scrapie.J Gen Virol.1994 Sep;75 ( Pt 9):2499-503.
| Cell experiment [1]: | |
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Cell lines |
peritoneal macrophages; HEK293 cells expressing TLR2 and CD14 |
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Preparation method |
The solubility of this compound in DMSO is >46.2mg/mL. General tips for obtaining a higher concentration: Please warm the tube at 37℃ for 10 minutes and/or shake it in the ultrasonic bath for a while. Stock solution can be stored below -20℃ for several months. |
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Reacting condition |
1, 2, and 4 μg/ml |
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Applications |
In peritoneal macrophages from CD14 knockout mice (C57BL/6 CD14–/–) and CD14 wild-type (C57BL/6 CD14+/+) mice, Amphotericin B failed to induce the production of TNF-α in macrophages from CD14–/– mice. HEK293 cells expressing TLR2 and CD14 responded more strongly to Amphotericin B (1, 2, and 4 μg/ml). |
| Animal experiment [2]: | |
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Animal models |
hamster scrapie model |
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Dosage form |
2.5 mg/kg; p.i. injection from 0 to 7 days |
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Application |
In hamsters infected intracerebrally with scrapie, Amphotericin B significantly prolonged the survival time by 14.7 days. |
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Other notes |
Please test the solubility of all compounds indoor, and the actual solubility may slightly differ with the theoretical value. This is caused by an experimental system error and it is normal. |
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参考文献: [1]. Sau K1,Mambula SS,Latz E,Henneke P,Golenbock DT,Levitz SM.The antifungal drug amphotericin B promotes inflammatory cytokine release by a Toll-like receptor- and CD14-dependent mechanism.J Biol Chem.2003 Sep 26;278(39):37561-8. Epub 2003 Jul 14. [2]. Demaimay R1,Adjou K,Lasmézas C,Lazarini F,Cherifi K,Seman M,Deslys JP,Dormont D.Pharmacological studies of a new derivative of amphotericin B, MS-8209, in mouse and hamster scrapie.J Gen Virol.1994 Sep;75 ( Pt 9):2499-503. |
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