Repurposing of respiratory drug theophylline againstCandida 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.

Antifungal Activity of Methylxanthines against Grapevine Trunk Diseases

“…Concerning theophylline, its mechanism of fungistatic activity would be similar, involving a damaging effect on the fungal cell wall and cell membrane. Singh et al [25] investigated the antifungal activity of theophylline against Candida spp. and mechanistic insights revealed that it induces membrane damage due to enhanced ionic disturbances and depleted ergosterol levels with a concomitant rise in membrane fluidity due to elevated flippase activity.…”

Antifungal Development and the Urgency of Minimizing the Impact of Fungal Diseases on Public Health

“…In the case of pathogenic fungi, drug repurposing emerged as a promising approach to combat C. neoformans , ,− Candida spp. (including C. auris ), ,− Aspergillus spp., Scedosporium and Lomentospora species, the chromoblastomycosis agents Fonsecaea pedrosoi , F. monophora , F. nubica , Cladophialophora carrionii , Phialophora verrucosa , Exophiala jeanselmei , E. dermatitidis , and Rhinocladiella similis , and the dimorphic fungi Sporothrix spp . These studies revealed a collection of molecules with potential to be applied in the treatment of the diseases caused by members of the above-mentioned genera.…”

Drug Repurposing in Medical Mycology: Identification of Compounds as Potential Antifungals to Overcome the Emergence of Multidrug-Resistant Fungi

“…Finally, theophylline is generally used for asthma or chronic obstructive pulmonary disease (COPD) and has been proposed to treat candidiasis as it had effects on cell membrane integrity [53].…”