Mannich base limits Candida albicans virulence by inactivating Ras-cAMP-PKA pathway

Abstract

Mannich bases and its derivatives are regarded as supreme pharmacophores in therapeutics. The study investigates the antimycotic potential of Mannich bases, 1-((1H-benzimidazol-1-yl) methyl) urea (C1) and 1-((3-hydroxynapthalen-2-yl) methyl) thiourea (C2), against Candida albicans. Biofilm and hyphal inhibitory activities of the Mannich bases were tested by crystal violet quantification, fluorescence imaging cAMP rescue, qRT PCR, and by molecular docking analysis. The compounds inhibited the biofilms of C. albicans and restrained the filamentation abilities of the pathogen. Structure-activity relationship studies revealed that the presence of urea or thiourea moiety in the tail section is essential for interacting with adenylate cyclase (AC). The Mannich bases seemed to block Ras-cAMP-PKA pathway by inhibiting second messenger activity required for hyphal induction and biofilm formation. In conclusion, the study warrants point-of-care testing of C1/C2 and provides a starting point for deriving several structurally modified Mannich bases which might plausibly replace the prevailing antimycotic drugs in future.

Catechol thwarts virulent dimorphism in Candida albicans and potentiates the antifungal efficacy of azoles and polyenes

“…To further evaluate the antihyphal and antibiofilm effect of catechol at transcriptomic level, qPCR analysis was performed. As previously discussed, Ras-cAMP-PKA pathway was found to play a vital role than the all other signal transduction pathways in C. albicans pathogenesis 53 . In this pathway, RAS1 act as positive regulator binds with CYR1 (adenylate cyclase) and thereby regulates the expression of several virulence genes responsible for filamentation and host cell invasion.…”

“…The hyphal formation in C. albicans necessarily involves two important pathways namely, Ras-dependent (Ras-cAMP-PKA) and Ras-independent (Ubr1-Cup9).As far as the pathogenesis and infection by C. albicans are concerned, yeast to hyphal transition has been mediated through the Ras-cAMP-PKA pathway 53 . In C. albicans , farnesol is the quorum sensing molecule , which naturally blocks the yeast to hyphae transition at relatively higher concentrations.…”

Catechol, a Natural Allelochemical Thwarts Virulent Dimorphism in Candida Albicans and Potentiates the Antifungal Efficacy of Azoles and Polyenes.

“…To further evaluate the antihyphal and antibio lm effect of catechol at transcriptomic level, qPCR analysis was performed. As previously discussed, Ras-cAMP-PKA pathway was found to play a vital role than the all other signal transduction pathways in C. albicans pathogenesis 53 . In this pathway, RAS1 act as positive regulator binds with CYR1 (adenylate cyclase) and thereby regulates the expression of several virulence genes responsible for lamentation and host cell invasion.…”

Molecular Mechanisms of Resistance to Antifungals in Candida albicans

“…A recently studied pathway as a potential target is the ionic homeostasis signalling pathway, which is central to the fungus survival by regulating gene expression, morphological transition, response to stress, and resistance to antifungals [84]. The Ras-cAMP-PKA signal transduction pathway is essential for cellular metabolism and controls morphogenesis, adhesion, and biofilm formation, making the inactivation of this signalling cascade attractive as a target for new antifungals [85].…”