Department of Pharmacognosy, Faculty of Pharmacy, Ain-Shams University, African Union Organization Street, Abbassia, Cairo, 11566, Egypt.
Microb Cell Fact. 2024 May 31;23(1):161. doi: 10.1186/s12934-024-02411-3.
Multi resistant fungi are on the rise, and our arsenal compounds are limited to few choices in the market such as polyenes, pyrimidine analogs, azoles, allylamines, and echinocandins. Although each of these drugs featured a unique mechanism, antifungal resistant strains did emerge and continued to arise against them worldwide. Moreover, the genetic variation between fungi and their host humans is small, which leads to significant challenges in new antifungal drug discovery. Endophytes are still an underexplored source of bioactive secondary metabolites. Many studies were conducted to isolate and screen endophytic pure compounds with efficacy against resistant yeasts and fungi; especially, Candida albicans, C. auris, Cryptococcus neoformans and Aspergillus fumigatus, which encouraged writing this review to critically analyze the chemical nature, potency, and fungal source of the isolated endophytic compounds as well as their novelty features and SAR when possible. Herein, we report a comprehensive list of around 320 assayed antifungal compounds against Candida albicans, C. auris, Cryptococcus neoformans and Aspergillus fumigatus in the period 1980-2024, the majority of which were isolated from fungi of orders Eurotiales and Hypocreales associated with terrestrial plants, probably due to the ease of laboratory cultivation of these strains. 46% of the reviewed compounds were active against C. albicans, 23% against C. neoformans, 29% against A. fumigatus and only 2% against C. auris. Coculturing was proved to be an effective technique to induce cryptic metabolites absent in other axenic cultures or host extract cultures, with Irperide as the most promising compounds MIC value 1 μg/mL. C. auris was susceptible to only persephacin and rubiginosin C. The latter showed potent inhibition against this recalcitrant strain in a non-fungicide way, which unveils the potential of fungal biofilm inhibition. Further development of culturing techniques and activation of silent metabolic pathways would be favorable to inspire the search for novel bioactive antifungals.
多药耐药真菌日益增多,而我们的储备化合物在市场上的选择有限,只有几种,如多烯类、嘧啶类似物、唑类、烯丙胺类和棘白菌素类。虽然这些药物中的每一种都有独特的作用机制,但抗真菌耐药菌株确实在世界各地出现并继续出现。此外,真菌与其宿主人类之间的遗传变异很小,这导致在新的抗真菌药物发现方面面临重大挑战。内共生菌仍然是生物活性次生代谢物的一个未充分探索的来源。许多研究都致力于分离和筛选对耐药酵母和真菌有效、特别是对白色念珠菌、耳念珠菌、新型隐球菌和烟曲霉的内生纯化合物;这鼓励我们撰写这篇综述,批判性地分析分离出的内生化合物的化学性质、效力和真菌来源,以及它们的新颖特征和可能的构效关系。在此,我们报告了 1980-2024 年间约 320 种抗白色念珠菌、耳念珠菌、新型隐球菌和烟曲霉的抗真菌化合物的全面清单,其中大部分是从与陆地植物有关的欧陆纲和Hypocreales 目真菌中分离出来的,这可能是由于这些菌株易于在实验室中培养。46%的综述化合物对白色念珠菌有活性,23%对新型隐球菌有活性,29%对烟曲霉有活性,只有 2%对耳念珠菌有活性。共培养被证明是一种有效的技术,可以诱导其他无菌培养或宿主提取物培养中不存在的隐性代谢物,其中 Irperide 是最有前途的化合物,MIC 值为 1μg/mL。耳念珠菌仅对 persephacin 和 rubiginosin C 敏感。后者以非杀真菌的方式对这种难治性菌株表现出强烈的抑制作用,揭示了抑制真菌生物膜的潜力。进一步发展培养技术和激活沉默的代谢途径将有利于激发对新型生物活性抗真菌药物的研究。