Feldman Mark, Sionov Ronit Vogt, Mechoulam Raphael, Steinberg Doron
Biofilm Research Laboratory, Faculty of Dental Medicine, Institute of Dental Sciences, The Hebrew University of Jerusalem, Jerusalem 9112002, Israel.
Medicinal Chemistry Laboratory, The Institute for Drug Research, School of Pharmacy, Faculty of Medicine, The Hebrew University of Jerusalem, Jerusalem 9112002, Israel.
Microorganisms. 2021 Feb 20;9(2):441. doi: 10.3390/microorganisms9020441.
is a common fungal pathogen in humans. Biofilm formation is an important virulence factor of infections. We investigated the ability of the plant-derived cannabidiol (CBD) to inhibit the formation and removal of fungal biofilms. Further, we evaluated its mode of action. Our findings demonstrate that CBD exerts pronounced time-dependent inhibitory effects on biofilm formation as well as disruption of mature biofilm at a concentration range below minimal inhibitory and fungicidal concentrations. CBD acts at several levels. It modifies the architecture of fungal biofilm by reducing its thickness and exopolysaccharide (EPS) production accompanied by downregulation of genes involved in EPS synthesis. It alters the fungal morphology that correlated with upregulation of yeast-associated genes and downregulation of hyphae-specific genes. Importantly, it represses the expression of virulence-associated genes. In addition, CBD increases ROS production, reduces the intracellular ATP levels, induces mitochondrial membrane hyperpolarization, modifies the cell wall, and increases the plasma membrane permeability. In conclusion, we propose that CBD exerts its activity towards biofilm through a multi-target mode of action, which differs from common antimycotic agents, and thus can be explored for further development as an alternative treatment against fungal infections.
是人类常见的真菌病原体。生物膜形成是感染的一个重要毒力因子。我们研究了植物源性大麻二酚（CBD）抑制真菌生物膜形成和清除的能力。此外，我们评估了其作用方式。我们的研究结果表明，在低于最小抑菌浓度和杀菌浓度的浓度范围内，CBD对生物膜形成以及成熟生物膜的破坏具有明显的时间依赖性抑制作用。CBD在多个层面发挥作用。它通过降低真菌生物膜的厚度和胞外多糖（EPS）产量来改变生物膜结构，同时下调参与EPS合成的基因表达。它改变真菌形态，这与酵母相关基因的上调和菌丝特异性基因的下调相关。重要的是，它抑制毒力相关基因的表达。此外，CBD增加活性氧（ROS）产生，降低细胞内ATP水平，诱导线粒体膜超极化，改变细胞壁，并增加质膜通透性。总之，我们认为CBD通过多靶点作用模式对生物膜发挥作用，这与常见的抗真菌药物不同，因此可作为抗真菌感染的替代治疗方法进一步开发探索。
