ABSTRACT

Introduction

The antifungal therapy currently available includes three major classes of drugs: polyenes, azoles and echinocandins. However, the clinical use of these compounds faces several challenges: while polyenes are toxic to the host, antifungal resistance to azoles and echinocandins has been reported.

Areas covered

Fungal sphingolipids (SL) play a pivotal role in growth, morphogenesis and virulence. In addition, fungi possess unique enzymes involved in SL synthesis, leading to the production of lipids which are absent or differ structurally from the mammalian counterparts. In this review, we address the enzymatic reactions involved in the SL synthesis and their relevance to the fungal pathogenesis, highlighting their potential as targets for novel drugs and the inhibitors described so far.

Expert opinion

The pharmacological inhibition of fungal serine palmitoyltransferase depends on the development of specific drugs, as myriocin also targets the mammalian enzyme. Inhibitors of ceramide synthase might constitute potent antifungals, by depleting the pool of complex SL and leading to the accumulation of the toxic intermediates. Acylhydrazones and aureobasidin A, which inhibit GlcCer and IPC synthesis, are not toxic to the host and effectively treat invasive mycoses, emerging as promising new classes of antifungal drugs.

中文翻译：

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真菌鞘脂：在毒力调节中的作用以及作为未来抗真菌治疗靶点的潜力。

摘要

介绍

目前可用的抗真菌治疗包括三大类药物：多烯类、唑类和棘白菌素类。然而，这些化合物的临床使用面临着一些挑战：虽然多烯对宿主有毒，但据报道对唑类和棘白菌素具有抗真菌耐药性。

覆盖领域

真菌鞘脂 (SL) 在生长、形态发生和毒力中发挥着关键作用。此外，真菌拥有参与 SL 合成的独特酶，导致产生哺乳动物对应物所不存在或结构不同的脂质。在这篇综述中，我们讨论了 SL 合成中涉及的酶反应及其与真菌发病机制的相关性，强调了它们作为迄今为止描述的新药和抑制剂的靶标的潜力。

专家意见

真菌丝氨酸棕榈酰转移酶的药理学抑制取决于特定药物的开发，因为多球壳菌素也针对哺乳动物酶。神经酰胺合酶抑制剂可能会消耗复杂的 SL 库并导致有毒中间体的积累，从而构成有效的抗真菌剂。酰腙和 aureobasidin A 可抑制 GlcCer 和 IPC 合成，对宿主无毒，可有效治疗侵袭性真菌病，成为有前景的新型抗真菌药物。