New anti-fungal compounds 1PB1 and 45R from Streptomyces chrestomyceticus ADP4 target exo-β-1,3-glucanase and...

The present study was aimed at understanding the mode of action of two newly reported anti-Candida compounds from Streptomyces chrestomyceticus strain ADP4: Phenyl 2'α,2'β,6'β-trimethyl cyclohexyl ketone (Chrestosyl cyclohexyl ketone; 1PB1) and trans-1-oxo-2,4-diacetylaminodecalin (Chrestosyl amino decalin; 45R). The docking studies revealed significant binding scores of CYP51 with 1PB1 (-7.4 kcal/mol) and with 45R (-7.6 kcal/mol). GC-MS sterol profiling of treated cells showed accumulation of lanosterol, confirming CYP51 inhibition. In vitro assays confirmed a consequent decrease in ergosterol biosynthesis, 69.92 ± 2.3% by 1PB1 and 55.48 ± 1.79% by 45R. In case of exo-β-1,3-glucanase, the binding scores were -8.4 kcal/mol with 1PB1 and -8.1 kcal/mol with 45R. Further, molecular dynamics simulations demonstrated that the complexes exhibited conformational stability, confirming strong and stable ligand binding compared to the apo forms. Inhibition of exo-β-1,3-glucanase as was confirmed through in vitro enzyme assays, wherein maximum inhibition of 94.6 ± 4.7% and 91.77 ± 1.7% were achieved at 52.7 µg/mL and 313.2 µg/mL of 1PB1 and 45R respectively. The results suggested that the compounds, 1PB1 and 45R, possessed a dual mode of action involving two cellular targets: CYP51 and exo-β-1,3-glucanase in Candida albicans.