Exometabolome variation in the fungal pathogen of humans <i>Candida albicans</i> reveals specificities at the genetic clade and strain levels

<i>Candida albicans</i> is a fungal pathobiont that thrives in different host niches and successfully confronts the host immune defenses. The success of <i>C. albicans</i> as a pathogen relies on a highly plastic metabolism, with examples of variations across isolates; however, detailed characterization of how <i>C. albicans</i> genetic diversity impacts the content of the metabolome is still missing. Here, we have implemented an NMR (nuclear magnetic resonance)-based high-throughput workflow to probe exometabolome variation in <i>in vitro</i> cultures of 96 clinical isolates spread across several genetic clusters (clades) that structure the <i>C. albicans</i> population. Our workflow allowed for batch analysis, with robust replication (six or more replicates) of the culture supernatants from these isolates. Results of this analysis highlighted the extent of metabolic divergence between clades (clade-specific variation) and within clades (isolate-specific variation). In particular, Clade 13 isolates (corresponding to the <i>Candida africana</i> isolates) showed metabolic specificities relative to isolates in other clades, notably non-consumption of trehalose and weak utilization of choline. Isolate-specific variation was mainly driven by metabolites involved in central carbon metabolism.IMPORTANCEThis study provides one of the most extensive analyses of <i>Candida albicans</i> exometabolome- comprising 96 isolates across all major genetic clades. By developing an NMR (nuclear magnetic resonance)-based, high-throughput workflow for the analysis of supernatants of <i>in vitro</i> cultured <i>C. albicans</i>, we demonstrated the extent of metabolic differences both between clades (clade-specific variation) and among isolates within each clade (isolate-specific variation). Isolates from Clade 13, which corresponds to <i>Candida africana</i>, exhibited distinct metabolic profiles compared to isolates from other clades, particularly in their inability to utilize trehalose and their reduced capacity to use choline. Variation among individual isolates was largely attributable to differences in metabolites associated with central carbon metabolism.