Amphotericin B (AmB) is one of the most effective antifungal drugs, with a strong, dose-dependent activity against most Candida and Aspergillus species responsible for life-threatening infections. However, AmB is severely toxic, which hinders its broad use. In this proof-of-concept study, we demonstrate that prodrugging AmB considerably decreases AmB toxicity without affecting its fungicidal activity. For this purpose, we modified the AmB structure by attaching a designer phosphate promoiety, thereby switching off its mode of action and preventing its toxic effects. The original fungicidal activity of AmB was then restored upon prodrug activation by host plasma enzymes. These AmB prodrugs showed a safer toxicity profile than commercial AmB deoxycholate in Candida and Aspergillus species and significantly prolonged larval survival of infected Galleria mellonella larvae. Based on these findings, prodrugging toxic antifungals may be a viable strategy for broadening the antifungal arsenal, opening up opportunities for targeted prodrug design.

中文翻译：

---

前药杀真菌两性霉素 B 可显著降低其毒性作用


两性霉素 B （AmB） 是最有效的抗真菌药物之一，对大多数导致危及生命的感染的念珠菌和曲霉菌属具有很强的剂量依赖性活性。然而，AmB 具有严重的毒性，这阻碍了其广泛使用。在这项概念验证研究中，我们证明 AmB 前药可显著降低 AmB 毒性，而不影响其杀真菌活性。为此，我们通过附加设计磷酸盐促进剂来修饰 AmB 结构，从而关闭其作用方式并防止其毒性作用。然后在宿主血浆酶激活前药后恢复 AmB 的原始杀真菌活性。这些 AmB 前药在念珠菌和曲霉菌属物种中显示出比商业 AmB 脱氧胆酸盐更安全的毒性特征，并且显着延长了受感染的 Galleria mellonella 幼虫的幼虫存活。基于这些发现，前药毒性抗真菌药可能是扩大抗真菌药库的可行策略，为靶向前药设计提供机会。