Beyond ergosterol: Strategies for combatting antifungal resistance in Aspergillus fumigatus and Candida auris
Beyond ergosterol: Strategies for combatting antifungal resistance in Aspergillus fumigatus and Candida auris
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DOI：
10.1016/j.tet.2023.133268
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发表时间：
2023-02-16
期刊：
影响因子：
2.1
通讯作者：
Wuest, William M.
中科院分区：
文献类型：
--
作者：
Cruz, Ricardo;Wuest, William M.
烟曲霉和耳念珠菌是历史上有问题的真菌病原体，造成全身感染和高死亡率，特别是在免疫功能低下的人群中。在过去的几十年里，三种抗真菌药物已经有效地治疗了这些真菌感染，但随着对这些化合物的耐药性的积累，它们的效力已经稳步下降。重要的是，在临床环境中观察到泛耐药的耳念珠菌菌株，使受影响的患者没有治疗选择和被判处死刑。正在进行的抗真菌药物发现管道中的许多化合物，类似于我们前面提到的三位一体中的化合物，都是基于麦角甾醇的结合或抑制。针对这一途径的抗真菌药物耐药性的反复报道表明，麦角甾醇依赖性抗真菌药物的优化可能不是长期的最佳解决方案。本综述旨在介绍几种具有新的或未充分开发的生物学靶点的天然产物，以及类似未充分利用的药物发现策略，以启发未来的生物学研究和药物化学运动。2023爱思唯尔有限公司版权所有。
Aspergillus fumigatus and Candida auris are historically problematic fungal pathogens responsible for systemic infections and high mortality rates, especially in immunocompromised populations. The three antifungal classes that comprise our present day armamentarium have facilitated efficacious treatment of these fungal infections in past decades, but their potency has steadily declined over the years as resistance to these compounds has accumulated. Importantly, pan-resistant strains of Candida auris have been observed in clinical settings, leaving affected patients with no treatment options and a death sentence. Many compounds in the ongoing antifungal drug discovery pipeline, similar to those within our aforementioned trinity, are predicated on the binding or inhibition of ergosterol. Recurring accounts of resistance to antifungals targeting this pathway suggest optimization of ergosterol-dependent anti-fungals is likely not the best solution for the long-term. This review aims to present several natural products with novel or underexplored biological targets, as well as similarly underutilized drug discovery strategies to inspire future biological investigations and medicinal chemistry campaigns.(c) 2023 Elsevier Ltd. All rights reserved.