A genome-scale metabolic model for the human pathogen Candida Parapsilosis and early identification of putative novel antifungal drug targets

Abstract

Candida parapsilosis is an emerging human pathogen whose incidence is rising worldwide, while an increasing number of clinical isolates display resistance to first-line antifungals, demanding alternative therapeutics. Genome-Scale Metabolic Models (GSMMs) have emerged as a powerful in silico tool for understanding pathogenesis due to their systems view of metabolism, but also to their drug target predictive capacity. This study presents the construction of the first validated GSMM for C. parapsilosis—iDC1003—comprising 1003 genes, 1804 reactions, and 1278 metabolites across four compartments and an intercompartment. In silico growth parameters, as well as predicted utilisation of several metabolites as sole carbon or nitrogen sources, were experimentally validated. Finally, iDC1003 was exploited as a platform for predicting 147 essential enzymes in mimicked host conditions, in which 56 are also predicted to be essential in C. albicans and C. glabrata. These promising drug targets include, besides those already used as targets for clinical antifungals, several others that seem to be entirely new and worthy of further scrutiny. The obtained results strengthen the notion that GSMMs are promising platforms for drug target discovery and guide the design of novel antifungal therapies.