Waikialoid A Suppresses Hyphal Morphogenesis and Inhibits Biofilm Development in Pathogenic Candida albicans

A chemically prolific strain of Aspergillus was isolated from a soil sample collected near Waikiki Beach, Honolulu, Hawaii. The fungus produced several secondary metabolites, which were purified and placed in our natural products library and were later screened for substances capable of inhibiting biofilm formation by Candida albicans. It was determined that one of the secondary metabolites from the Hawaiian fungal isolate, a new complex prenylated indole alkaloid named waikialoid A (1), inhibited biofilm formation with an IC50 value of 1.4 μM. Another structurally unrelated, presumably polyketide metabolite, waikialide A (15), also inhibited C. albicans biofilm formation, but was much less potent (IC50 value of 32.4 μM). Microscopy studies revealed that compound 1 also inhibited C. albicans hyphal morphogenesis. While metabolite 1 appears ineffective at disrupting preformed biofilms, the accumulated data indicate that the new compound may exert its activity against C. albicans during the early stages of surface colonization involving cell adherence, hyphal development, and/or biofilm assembly. Unlike some other stephacidin/notoamide compounds, metabolite 1 was not cytotoxic to fungi or human cells (up to 200 μM), which makes this an intriguing model compound for studying the adjunctive use of biofilm inhibitors in combination with standard antifungal antibiotics.

从夏威夷州火奴鲁鲁市威基基海滩附近采集的土壤样本中，分离得到一株化学合成能力旺盛的曲霉属（Aspergillus）菌株。该真菌可产生多种次级代谢产物，经纯化后被纳入本实验室的天然产物库，后续针对能够抑制白色念珠菌（Candida albicans）生物被膜形成的活性物质开展了筛选。研究发现，这株夏威夷来源真菌分离物的一种次级代谢产物——命名为waikialoid A（1）的新型复杂异戊烯基化吲哚生物碱（prenylated indole alkaloid），其半数抑制浓度（IC50）为1.4 μM，可有效抑制生物被膜形成。另一种结构无关、推测属于聚酮类（polyketide）的代谢产物waikialide A（15），同样可抑制白色念珠菌的生物被膜形成，但活性较弱，其IC50值为32.4 μM。显微镜研究表明，化合物1还可抑制白色念珠菌的菌丝形态发生（hyphal morphogenesis）。尽管代谢物1似乎无法破坏预形成的生物被膜，但现有研究数据表明，该新型化合物可能在表面定植的早期阶段（涉及细胞黏附、菌丝发育和/或生物被膜组装）发挥抗白色念珠菌活性。与部分其他斯蒂芬菌素/诺托酰胺（stephacidin/notoamide）类化合物不同，代谢物1对真菌或人类细胞（最高浓度可达200 μM）无细胞毒性，这使其成为研究将生物被膜抑制剂与标准抗真菌抗生素联合使用的辅助疗法的极具潜力的模型化合物。