Second-Generation Antidiabetic Sulfonylureas Inhibit Candida albicans and Candidalysin-Mediated Activation of the NLRP3 Inflammasome

Repurposing of currently approved medications is an attractive option for the development of novel treatment strategies against physiological and infectious diseases. The antidiabetic sulfonylurea glyburide has demonstrated off-target capacity to inhibit activation of the NLRP3 inflammasome in a variety of disease models, including vaginal candidiasis, caused primarily by the fungal pathogen Candida albicans. Therefore, we sought to determine which of the currently approved sulfonylurea drugs prevent the release of interleukin 1 beta (1-1 beta), a major inflammasome effector, during C. albicans challenge of the human macrophage-like THP1 cell line. Findings revealed that the second-generation antidiabetics (glyburide, glisoxepide, gliquidone, and glimepiride), which exhibit greater antidiabetic efficacy than prior iterations, demonstrated anti-inflammatory effects with various degrees of potency as determined by calculation of 50% inhibitory concentrations (IC(50)s). These same compounds were also effective in reducing IL-1 beta release during noninfectious inflammasome activation (e.g., induced by lipopolysaccharide (LPS] plus ATP), suggesting that their anti-inflammatory activity is not specific to C. albicans challenge. Moreover, treatment with sulfonylurea drugs did not impact C. albicans growth and filamentation or THP1 viability. Finally, the use of ECE1 and Candidalysin deletion mutants, along with isogenic NLRP3(-/-) cells, demonstrated that both Candidalysin and NLRP3 are required for IL-1 beta secretion, further confirming that sulfonylureas suppress inflammasome signaling. Moreover, challenge of THP1 cells with synthetic Candidalysin peptide demonstrated that this toxin is sufficient to activate the inflammasome. Treatment with the experimental inflammasome inhibitor MCC950 led to similar blockade of IL-1 beta release, suggesting that Candidalysin-mediated inflammasome activation can be inhibited independently of potassium efflux. Together, these results demonstrate that the second-generation antidiabetic sulfonylureas retain anti-inflammatory activity and may be considered for repurposing against immunopathological diseases, including vaginal candidiasis.