In-vitro and In-silico Investigations of Recent and Traditional Antifungal Agents as Inhibitors of Fungal Chitin Synthesis

Abstract

Invasive fungal infections demand novel approaches targeting cell wall components, particularly poly(β)-(1→4)-(N-acetyl-D-glucosamine) (chitin) and β-glucan. This study evaluated Caspofungin, Micafungin, Ibrexafungerp, and Nikkomycin Z against Aspergillus fumigatus and Candida albicans. Moreover, the binding affinity and interaction profiles of Caspofungin, Micafungin, Ibrexafungerp (SCY-078), and Nikkomycin Z against two crystallographic targets: Calcineurin A from A. fumigatus (PDB ID: 6TZ7) and poly(β)-(1→4)-(N-acetyl-D-glucosamine) synthase 2 from C. albicans (PDB ID: 7STN), using Molecular Operating Environment (MOE) docking were evaluated. Micafungin showed highest monotherapy activity (21 ± 0.8 and 25 ± 0.9 mm), while Micafungin–Ibrexafungerp produced maximal inhibition (29 ± 1.0 and 28 ± 0.9 mm), indicating synergistic cell wall disruption and species-dependent variability. Docking scores revealed that Micafungin exhibited the strongest binding toward 6TZ7 (S = −10.96 kcal/mol) and 7STN (S = −13.82 kcal/mol). Nikkomycin Z demonstrated multiple hydrogen bonding interactions within the catalytic pocket of poly(β)-(1→4)-(N-acetyl-D-glucosamine) synthase 2, consistent with its known mechanism as a poly(β)-(1→4)-(N-acetyl-D-glucosamine) synthase inhibitor. These findings support differential binding behaviors of echinocandins, triterpenoid glucan synthase inhibitors, and poly(β)-(1→4)-(N-acetyl-D-glucosamine) synthase inhibitors toward key fungal enzymes and provide structural insight into their antifungal mechanisms.