Manogepix induces the formation of viable aggregates in Candida auris at concentrations above the MIC

Candida auris has emerged as a major global health threat due to its multidrug resistance. Manogepix has demonstrated promising activity against antifungal-resistant yeasts and thus represents a promising alternative. The aim of this study was to characterize the activity of manogepix against several strains of C. auris. Time-kill curve (TKC) analyses were conducted on C. auris strains B11103, B11221, and B11244. TKCs were assessed both on YPD agar plates and by flow cytometry (FCM). FCM analysis enabled the quantification and classification of yeast cells based on FSC/SSC, propidium iodide (PI; membrane integrity marker) staining, and morphological features. Aggregate structure, staining patterns and their reversibility were also investigated. Interestingly, formation of yeast aggregates was observed following exposure to manogepix at concentration ranging from the minimum inhibitory concentration (MIC; 0.008 – 0.016 mg/L) to 8x MIC (0.06 – 0.125 mg/L). Confocal microscopy revealed that cells largely retained intact morphological features inside the aggregate with only a limited number of cells within the aggregates being PI-positive. Analyses also suggested that C. auris aggregates retained the ability to grow on agar and to dissociate after treatment removal. Manogepix exposure induced formation of viable aggregates in C. auris at concentrations above MIC. These aggregates, previously described under echinocandin exposure, could be associated with tolerance. Our data suggest that manogepix treatment for C. auris may require concentrations well above the MIC to prevent formation of viable aggregates potentially linked to antifungal tolerance.