Penta-O-Galoil-Β-D-Glicose (PGG) potencializa a atividade antifúngica do fluconazol contra Trichosporon asahii: análises in silico e in vitro

Abstract

Trichosporon asahii is an opportunistic pathogen associated with severe systemic infections, often resistant to conventional antifungal agents. This study investigated the antifungal potential of penta-O-galloyl-B-D-glucose (PGG), alone and in combination with fluconazole (FLZ), through in silico, in vitro. In silico analyses included the prediction of pharmacokinetic properties, toxicity, and drug-likeness. In vitro assays comprised broth microdilution to determine the minimum inhibitory concentration (MIC), checkerboard testing for synergy assessment, and quantification of cell viability in developing and mature biofilms. Molecular docking evaluated the interaction of PGG with Erg11 and Erg2 enzymes, key targets in the ergosterol biosynthesis pathway. The results are presented in two chapters: (1) a systematic review article on the in vitro and in vivo antimicrobial effects of PGG, which demonstrated broad activity, particularly against viruses and multidrug-resistant strains, with effects including biofilm inhibition, blockage of microbial entry and replication, enzyme inhibition, and modulation of cellular pathways; and (2) an experimental study reporting the synergistic action of PGG with FLZ against 7. asahii in in silico and in vitro analyses. Computational predictions indicated low hepatotoxicity and a favorable pharmacokinetic profile, although with limited gastrointestinal absorption. In in vitro assays, PGG exhibited an MIC of 1000 µg/ml.. fungicidal activity, and synergy with FLZ (FICI=0.31), reducing the required concentrations of PGG and FLZ by 64- and 4-fold, respectively; two tested combinations inhibited >70% of fungal growth and displayed antibiofilm activity, even at subinhibitory concentrations. Docking analysis revealed high affinity for Erg11 and Erg2. suggesting a dual mechanism of action. These findings support the potential of PGG as an adjuvant candidate for the treatment of systemic trichosporonosis and warrant further validation in in vivo models.