Repurposing of respiratory drug theophylline against Candida albicans: mechanistic insights unveil alterations in membrane properties and metabolic fitness

Abstract

Aims: Drug repurposing is an attractive chemotherapeutic strategy that serves to make up for the inadequacy of current antifungal drugs. The present study aims to repurpose theophylline (THP) against Candida albicans. THP is a methylxanthine derived from cocoa beans and tea extracts, generally used as the first-line drug for asthma and other respiratory disorders. Methods and Results: We investigated the antifungal activity of THP against C. albicans and non-albicans species. Mechanistic insights revealed that THP induces membrane damage. Enhanced ionic disturbances and depleted ergosterol levels with the concomitant rise in membrane fluidity due to elevated flippase activity confirmed the membrane damaging effect. THP impeded the metabolic adaptability of C. albicans by inhibiting malate synthase and isocitrate lyase enzymes of the glyoxylate cycle. In vivo efficacy of THP was depicted by increased survival of C. albicans infected Caenorhabditis elegans model. Conclusions: This study elucidates the antifungal potential of THP with mechanistic insights. Significance and Impact of the Study: This study unveils the antifungal potential of THP, a known respiratory drug that can be further utilized for a wider range of applications such as combating fungal infections. The effect of THP with the known antifungal drugs can be exploited in the combinatorial drug approach for treating candidiasis.