Antifungal and antibiofilm action of triphenylphosphonium-conjugated curcumin on Candida albicans: Efficacy and activity mechanisms

Natural compounds and their derivatives have become the source of new generation antimicrobials to address the growing concern of antimicrobial resistance. The polyphenols present in the edible crops are traditionally used for preventing infections. Conjugation with cationic triphenylphosphonium (TPP) is used for synthesizing antimicrobials and to evade resistance development. Here, we report the antifungal and antibiofilm efficacy of TPP-conjugated curcumin (TPP-curcumin) on standard and clinical strains of C. albicans for the first time in comparison with native curcumin and common antifungal drugs. TPP-curcumin showed strong antifungal activity on Candida strains with MIC and MFC values of 3.75 and 5 μM, respectively. The antifungal and antibiofilm activity of TPP-curcumin was several fold effective than native curcumin and fluconazole. In vitro time-kill kinetics revealed complete killing of 106 cells mL−1 within 9 h exposure to TPP-curcumin. TPP-curcumin exhibited biofilm prevention, killing of biofilm-cells and biofilm dispersal activities. The biological activity measurements demonstrated that TPP-curcumin induces cell membrane damage, reactive oxygen species generation, mitochondrial dysfunction and inhibition of NAD(P)H-dependent dehydrogenases in C. albicans cells. The yeast to hyphal growth transition pivotal to pathogenesis and biofilm formation was strongly inhibited by TPP-curcumin. Together, these data demonstrated that TPP-curcumin elicits strong antifungal and antibiofilm activities by impacting multiple cellular targets. The TPP-conjugation enhanced the solubility and biofilm prevention activities in drug-resistant C. albicans strains. The strong antibiofilm activity together with impact on multiple cellular targets is promising for considering TPP-curcumin for developing or augmenting antifungal therapies for preventing drug-resistant Candida infections.