Aripiprazole repurposed as an inhibitor of biofilm formation and sterol biosynthesis in multidrug-resistant Candida albicans

Int J Antimicrob Agents. 2019 Oct;54(4):518-523. doi: 10.1016/j.ijantimicag.2019.05.016. Epub 2019 Jun 5.

Abstract

Drug repurposing is an anticipative chemotherapeutic strategy that accentuates the inadequacy of antifungal drugs. The study identifies an antipsychotic drug, aripiprazole, as a biofilm and hyphal inhibitor of Candida albicans. Microtitre plate biofilm inhibition, metabolic activity and hyphal inhibitory assays were used to assess the potency of aripiprazole; and filipin staining, reactive oxygen species staining, cAMP rescue, propidium iodide staining, computational studies and qRT-PCR assays were used to elucidate its mode of action. The study revealed aripiprazole functioned in a manner similar to standard azoles, particularly the imidazole, ketoconazole, by inhibiting pseudohyphal formation during the early stages of hyphal development. The action of aripiprazole on C. albicans was dose-dependent and it exhibited varied mechanisms of action at low and high dosages. At low dosage, aripiprazole outperformed ketoconazole in terms of inhibiting biofilm formation, hyphal filamentations, and yeast flocculation, whereas at higher dosage it mimicked ketoconazole. This study illustrates the anti-candidal potential and mechanistic activities of aripiprazole, and indicates the future use of this drug as an anti-biofilm agent.

Keywords: Aripiprazole; Azoles; Biofilm; C. albicans; Ergosterol; Filipin.

MeSH terms

  • Antifungal Agents / pharmacology*
  • Aripiprazole / pharmacology*
  • Biofilms / drug effects*
  • Biofilms / growth & development*
  • Candida albicans / drug effects*
  • Candida albicans / growth & development
  • Cell Adhesion / drug effects
  • Dose-Response Relationship, Drug
  • Drug Repositioning*
  • Hyphae / drug effects
  • Hyphae / growth & development
  • Microbial Sensitivity Tests
  • Sterols / antagonists & inhibitors*

Substances

  • Antifungal Agents
  • Sterols
  • Aripiprazole