Proposed mechanism of a novel small molecule antifungal for Candida

Abstract

OBJECTIVE: Candida infections are major problem in immunocompromised populations. The limited number of antifungals and emergence of drug-resistant strains have posed a huge clinical challenge and highlighted the dire need for novel antifungal agents with new mechanism of action. Recently, a high-throughput screening of a library with 50,240 small molecules had led to our discovery of an antifungal small molecule (named “SM21”). Thereafter, SM21 was demonstrated to be a promising lead compound with potent in vitro and in vivo efficacies (US provisional patent No: 61733094). Aim of this study was to investigate the mechanism of action of SM21 by transcriptomic and proteomic approaches. METHOD: The SM21-induced global differential transcriptional and proteomic profiles were analyzed by microarray (with Filgen® Array for C. albicans) and label-free quantitative mass-spectrometry respectively. The significantly overrepresented gene ontology (GO) terms of the differentially expressed genes and proteins were assessed by GO enrichment analysis. RESULT: Among the SM21-induced differential transcriptome, the GO term “cell wall organization” was significantly overrepresented. The involved genes were shown to affect the biosynthesis of β-1,3-glucan, β-1,6-glucan and mannoprotein, the major components of Candida cell wall. Moreover, the ERG gene family, which is involved in the synthesis of ergosterol, the important component of the fungal plasma membrane, was significantly differentially regulated by SM21. The GO terms “cellular component organization and biogenesis” and “carbohydrate metabolic process” were significantly overrepresented in the SM21-induced proteome. Examples of the proteins involved were Gfa1p, Psa2p, Gal10p and Pmi1p. Regulation of these markers suggested that SM21 affected the Candida cell wall integrity. CONCLUSION: Taken together, it was proposed that, our new discovery SM21, affects the Candida cell membrane as well as the cell wall. This novel antifungal small molecule would be a valuable addition to the current limiting arsenal of antifungal agents.