Proton pump inhibitors act synergistically with fluconazole against resistant Candida albicans

Area of Science:

• Mycology
• Pharmacology
• Infectious Diseases

Background:

• Rising incidence of antifungal resistance in Candida isolates, particularly Candida albicans.
• Need for novel strategies to overcome drug resistance in fungal infections.
• Previous studies indicated potential antifungal effects of proton pump inhibitors (PPIs).

Purpose of the Study:

• To investigate the synergistic interactions between clinically used PPIs and fluconazole against resistant Candida albicans.
• To evaluate the efficacy of this combination therapy both in vitro and in vivo.
• To elucidate the underlying mechanisms of action for PPIs in sensitizing Candida to fluconazole.

Main Methods:

• In vitro susceptibility testing of PPIs and fluconazole against Candida albicans planktonic cells and biofilms.
• In vivo efficacy assessment using Galleria mellonella infection model.
• Mechanism studies focusing on efflux pump activity, phospholipase inhibition, and morphology switching.

Main Results:

• PPIs demonstrated synergistic activity with fluconazole, significantly reducing the minimum inhibitory concentration of fluconazole against resistant Candida albicans.
• Combination therapy markedly improved survival rates and reduced tissue damage in infected Galleria mellonella larvae compared to fluconazole monotherapy.
• PPIs were found to suppress efflux pump activity and inhibit key virulence factors like phospholipase and morphology switching.

Conclusions:

• Clinically relevant PPIs can act as effective antifungal sensitizers when combined with fluconazole against resistant Candida albicans.
• The synergistic effect is mediated by the suppression of common resistance mechanisms and virulence factors.
• This combination therapy presents a promising new approach for treating candidiasis caused by drug-resistant strains.