New insights on Drug's design against candidiasis on the fructose biphosphate aldolase (Fba1) and the pyruvate kinase (Pk) of Candida glabrata

Abstract

Candida glabrata is well known to be the second most common cause of invasive candidiasis (IC) within immunocompromised and hospitalized patients, after Candida albicans. Candida species adhere to host cells and implanted medical devices by means of cell wall proteins (CWP), of which the moonlight proteins have recently been described and are of particular importance because they have been identified in response to various virulence and/or pathogenic factors. Among the identified CWP moonlights, fructose-bisphosphate aldolase (Fba1) and pyruvate kinase (Pk) have been observed to confer immune protection against C. albicans and C. glabrata in a mouse model. In other pathogens, these proteins have been used as therapeutic targets. As the treatment of IC has been based on four main drug classes for decades, the Candida species has developed resistance mechanisms. In addition, C. glabrata has an innate resistance to the antifungal drugs, which makes the treatment of IC by this pathogen difficult. It is essential to have new formulations that allow new treatments of patients affected by this pathogen, so new targets with antifungal activity is of primary necessity. For this purpose, in this study we propose the moonlight CWPs Fba1 and Pk as novel candidates for drug targets. Using structural modeling, virtual database analysis, in vitro susceptibility tests, and enzymatic activity assays, we propose the use of new chemical molecules as potential antifungals against C. glabrata. In this sense, we chose to evaluate three chemical molecules (FE1, FE2 and FE3), whose chemical structure gives them the possible molecular leadership against Fba1 and Pk. Through the susceptibility experiments, our data showed that of the three molecules evaluated, FE1 was the best ligand against C. glabrata. We also found that Fba1 and Pk of C. glabrata had the characteristics of therapeutic targets against IC. In the present work, considering a group of tools in silico and experiments in vitro it was possible to identify the best candidate molecule as a possible antifungal for the treatment of IC caused by C. glabrata.