Antibiofilm potential of 6-methoxymellein from geranium-associated Aspergillus caespitosus endophyte against clinical isolates of dermatophytes: Phytochemical, in silico and in vitro investigation

Dermatophytes are saprophytic fungi which invade the skin and contribute to the pathogenesis of Tinea corporis. Dermatophytes are resistant to conventional antifungal agents due to biofilm formation, that's why effective therapy is still urgently needed. The edible aromatic plant, Pelargonium graveolens, is known for antimicrobial efficacies, and is extensively colonized by endophytic fungi with potent bio-efficacies. Aspergillus caespitosus AUMC 14405 was isolated from P. graveolens leaves and subjected to GC/MS analysis which led to the tentative identification of 27 metabolites, as well as phytochemical investigation which led to the isolation of 8 compounds. The in silico-based antifungal investigation highlighted 6-methoxymellein as a potent inhibitor of Trichophyton rubrum (a tinea corporis clinical isolate) growth with a MIC of 6.25 µg/ml, compared to fluconazole with a MIC of 25 µg/ml. Interestingly, 6 methoxy mellein exhibited 16.54 % inhibition of biofilm formation compared to fluconazole (0.36 %) at 1.56 µg/ml (P < 0.001) as well as 68.38 % inhibition compared to fluconazole (39.70 %) at 200 µg/ml (p ≤ 0.005). Our results revealed that 6-methoxymellein inhibits the fungal growth of T. rubrum isolates and inhibits their biofilm formation via hyphal disintegration. This may be attributed to targeting 1,3-β-glucan synthase and Δ-14-sterol reductase responsible for maintaining cell wall integrity and ergosterol biosynthesis, which was further confirmed via docking analysis. The study highlights 6-methoxymellein, the vital crop biocide, as a promising antifungal candidate to eradicate therapy-resistant cases of biofilm forming dermatophytes, with the need for further processing for mechanistic analysis, animal testing and clinical trials.