Instituto de Biología Funcional y Genómica and Departamento de Microbiología y Genética, Consejo Superior de Investigaciones Científicas (CSIC)/Universidad de Salamanca, Salamanca, Spain.
Área Farmacognosia, Facultad de Ciencias Bioquímicas y Farmacéuticas, Universidad Nacional de Rosario, Suipacha 531, 2000 Rosario, Argentina.
Phytomedicine. 2021 Jul 15;88:153556. doi: 10.1016/j.phymed.2021.153556. Epub 2021 Mar 27.
During the last three decades systemic fungal infections associated to immunosuppressive therapies have become a serious healthcare problem. Clinical development of new antifungals is an urgent requirement. Since fungal but not mammalian cells are encased in a carbohydrate-containing cell wall, which is required for the growth and viability of fungi, the inhibition of cell wall synthesizing machinery, such as β(1,3)-D-glucan synthases (GS) and chitin synthases (CS) that catalyze the synthesis of β(1-3)-D-glucan and chitin, respectively, represent an ideal mode of action of antifungal agents. Although the echinocandins anidulafungin, caspofungin and micafungin are clinically well-established GS inhibitors for the treatment of invasive fungal infections, much effort must still be made to identify inhibitors of other enzymes and processes involved in the synthesis of the fungal cell wall.
Since natural products (NPs) have been the source of several antifungals in clinical use and also have provided important scaffolds for the development of semisynthetic analogues, this review was devoted to investigate the advances made to date in the discovery of NPs from plants that showed capacity of inhibiting cell wall synthesis targets. The chemical characterization, specific target, discovery process, along with the stage of development are provided here.
An extensive systematic search for NPs against the cell wall was performed considering all the articles published until the end of 2020 through the following scientific databases: NCBI PubMed, Scopus and Google Scholar and using the combination of the terms "natural antifungals" and "plant extracts" with "fungal cell wall".
The first part of this review introduces the state of the art of the structure and biosynthesis of the fungal cell wall and considers exclusively those naturally produced GS antifungals that have given rise to both existing semisynthetic approved drugs and those derivatives currently in clinical trials. According to their chemical structure, natural GS inhibitors can be classified as 1) cyclic lipopeptides, 2) glycolipids and 3) acidic terpenoids. We also included nikkomycins and polyoxins, NPs that inhibit the CS, which have traditionally been considered good candidates for antifungal drug development but have finally been discarded after enduring unsuccessful clinical trials. Finally, the review focuses in the most recent findings about the growing field of plant-derived molecules and extracts that exhibit activity against the fungal cell wall. Thus, this search yielded sixteen articles, nine of which deal with pure compounds and seven with plant extracts or fractions with proven activity against the fungal cell wall. Regarding the mechanism of action, seven (44%) produced GS inhibition while five (31%) inhibited CS. Some of them (56%) interfered with other components of the cell wall. Most of the analyzed articles refer to tests carried out in vitro and therefore are in early stages of development.
This report delivers an overview about both existing natural antifungals targeting GS and CS activities and their mechanisms of action. It also presents recent discoveries on natural products that may be used as starting points for the development of potential selective and non-toxic antifungal drugs.
在过去的三十年中，与免疫抑制疗法相关的系统性真菌感染已成为严重的医疗保健问题。新抗真菌药物的临床开发是一项紧迫的要求。由于真菌而不是哺乳动物细胞被包裹在含有碳水化合物的细胞壁中，细胞壁的生长和存活都需要它，因此抑制细胞壁合成机制，例如催化β(1-3)-D-葡聚糖和几丁质合成的β(1,3)-D-葡聚糖合成酶(GS)和几丁质合成酶(CS)，代表了抗真菌药物的理想作用模式。虽然棘白菌素类化合物中的安尼芬净、卡泊芬净和米卡芬净已在临床上被广泛用作治疗侵袭性真菌感染的 GS 抑制剂，但仍需努力寻找其他参与真菌细胞壁合成的酶和过程的抑制剂。
由于天然产物(NPs)一直是临床应用中几种抗真菌药物的来源，并且也为半合成类似物的开发提供了重要的支架，因此，本综述旨在调查迄今为止从具有抑制细胞壁合成靶标能力的植物中发现 NPs 的进展。提供了化学特征、特定靶标、发现过程以及开发阶段。
通过以下科学数据库对针对细胞壁的 NPs 进行了广泛的系统搜索，考虑了截至 2020 年底发表的所有文章：NCBI PubMed、Scopus 和 Google Scholar，并使用了“天然抗真菌剂”和“植物提取物”与“真菌细胞壁”的组合。
本综述的第一部分介绍了真菌细胞壁的结构和生物合成的最新进展，并专门考虑了那些已产生现有半合成批准药物和目前处于临床试验阶段的衍生物的天然产生的 GS 抗真菌药物。根据其化学结构，天然 GS 抑制剂可分为 1）环状脂肽、2）糖脂和 3）酸性萜类化合物。我们还包括 nikkomycins 和 polyoxins，它们是抑制 CS 的 NPs，由于在临床试验中失败，它们一直被认为是抗真菌药物开发的良好候选药物，但最终被淘汰。最后，综述重点介绍了植物衍生分子和提取物在抗真菌细胞壁方面的最新发现。因此，这项搜索产生了 16 篇文章，其中 9 篇涉及纯化合物，7 篇涉及对真菌细胞壁具有活性的植物提取物或馏分。关于作用机制，有 7 种(44%)产生了 GS 抑制作用，5 种(31%)抑制了 CS。其中一些(56%)干扰了细胞壁的其他成分。分析的大多数文章都涉及体外进行的测试，因此处于早期开发阶段。
本报告概述了针对 GS 和 CS 活性的现有天然抗真菌药物及其作用机制。它还介绍了天然产物的最新发现，这些发现可能成为开发潜在选择性和非毒性抗真菌药物的起点。
