Inhibition of Candida albicans yeast-to-hypha transition and virulence by cyclic dipeptides derived from probiotic...

Candida albicans, a common opportunistic fungal pathogen, poses serious clinical challenges due to multidrug resistance and limited therapeutic options. In this study, four cyclic dipeptides (diketopiperazines, DKPs), cyclo(L-Pro-L-Leu), cyclo(L-Pro-L-Val), cyclo(D-Pro-L-Phe), and cyclo(L-Pro-D-Tyr) were isolated from the probiotic bacterium Aeromonas veronii strainV03 and evaluated for antimicrobial and antivirulence activities. All DKPs exhibited broad-spectrum antibacterial and antifungal effects, with cyclo(D-Pro-L-Phe) exhibiting particularly potent activity against C. albicans, with minimum inhibitory concentration (MIC) values lower than the standard antifungal amphotericin B under the tested conditions. The DKPs also significantly inhibited key virulence traits of C. albicans, including yeast-to-hypha transition, secreted hydrolase activities (aspartic proteases and phospholipases), and biofilm formation, in a dose-dependent manner. Molecular docking revealed strong binding affinities of the DKPs to virulence-associated proteins, including ERG1, ERG11, HGC1, HWP1, SAP2, SAP5, and ALS1, consistent with their observed antivirulence effects. These findings highlight DKPs from A. veronii V03 as promising antivirulence agents and potential leads for alternative antifungal therapeutics.