Abstract
Farnesol, a self-secreted quorum-sensing molecule (QSM) of Candida albicans, has been known to limit yeast-to-hyphal transition by blocking the RAS1–cAMP–PKA pathway. In a similar fashion, certain bacterial QSMs have also been reported to be successful in attenuating C. albicans biofilm and hyphal formation at relatively high cell density. This prompted us to investigate the antihyphal efficacy of certain bacterial QSMs through virtual docking against seminal drug targets, viz., CYCc and RAS1, that have been reported to be the hallmark players in C. albicans dimorphic virulence cascade. Against this backdrop, 64 QSMs belonging to five different bacterial QS signaling systems were subjected to initial virtual screening with farnesol as reference. Data of the virtual screening unveiled QSMs belonging to diketopiperazines (DKPs), i.e., 3-benzyl-6-isobutylidene-2,5-piperazinedione (QSSM 1157) and cyclo(l-Pro-l-Leu) (QSSM 1112), as potential inhibitors of CYCc and RAS1 with binding energies of −8.2 and −7.3 kcal mol−1, respectively. Further, the molecular dynamics simulations (for 50 ns) of CYCc-QSSM 1157 and RAS1-QSSM 1112 complexes revealed the mean ligand root mean square deviation (RMSD) values of 0.35 and 0.27 Å, respectively, which endorsed the rigid nature, less fluctuation in binding stiffness, and conformation of binding complexes. Furthermore, the identified two QSMs were found to be good in solubility, absorption, and permeation and less toxic in nature, as revealed by pharmacokinetics and toxicity analyses. In addition, the in vitro antihyphal assays using liquid and solid media, germ-tube experiment, and microscopic analysis strongly validated DKP-QSSM 1112 as a promising inhibitor of hyphal transition. Taken together, the present study unequivocally proves that DKPs can be used as potent inhibitors of C. albicans virulence dimorphism.
Highlights
Despite the advances in modern medicine, the management of infectious diseases has become more challenging, as microbial pathogens consistently break down every antimicrobial wall through a phenomenon called “antimicrobial resistance” (Llor and Bjerrum, 2014; Dadgostar, 2019)
Few reports have been focused on the competitive antagonistic interactions between bacteria and C. albicans, which signify that bacterial quorum-sensing molecule (QSM) could play a key role in targeting and blocking yeast-to-hyphal transition (Hogan et al, 2004; Nickerson and Atkin, 2017)
This intertaxon chemical communication between bacteria and fungi prompted us to investigate the effect of bacterial QSMs as natural hyphal inhibitors against C. albicans through in silico approach
Summary
Despite the advances in modern medicine, the management of infectious diseases has become more challenging, as microbial pathogens consistently break down every antimicrobial wall through a phenomenon called “antimicrobial resistance” (Llor and Bjerrum, 2014; Dadgostar, 2019). Among the various fungal species, Candida albicans is the most representative pathogen at clinical setup, which causes severe contagious infections in humans (Jha and Kumar, 2018). C. albicans is a diploid polymorphic fungus that asymptomatically colonizes various niches of healthy humans as commensal. Given the opportunity, C. albicans turns into a pathogen and causes clinically diverse infections, especially in individuals with disturbed immune surveillance or other debilitating conditions (Garcia et al, 2021). Identifying molecules with potency to target dimorphic switching has been considered as one of the promising alternatives to effectively combat the infections associated with antifungal-resistant C. albicans by nullifying the phenomenon of selection pressure
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