The effect of the novel antifungal drug F901318 (Olorofim) on the growth and viability of Aspergillus fumigatus [PublishAheadOfPrint]

F901318 (olorofim) is a novel antifungal drug that is highly active against Aspergillus species. Belonging to a new class of antifungals called the orotomides, F901318 targets dihydroorotate dehydrogenase (DHODH) in the de novo pyrimidine biosynthesis pathway. In this study, the antifungal effects of F901318 against Aspergillus fumigatus were investigated. Live-cell imaging revealed that, at a concentration of 0.1 μg/ml, F901318 completely inhibited germination, but conidia continued to expand by isotropic growth for >120 h. When this low F901318 concentration was applied to germlings or vegetative hyphae their elongation was completely inhibited within 10 h. Staining with the fluorescent viability dye bis-(1,3-dibutylbarbituric acid) trimethine oxonol (DiBAC) showed that prolonged exposure to F901318 (>24 h) led to vegetative hyphal swelling and a decrease in hyphal viability through cell lysis. The time-dependent killing of F901318 was further confirmed by measuring fungal biomass and growth rate in liquid culture. Compared to the untreated control, the ability of hyphal growth to recover in drug-free medium after 24h exposure to F901318 was strongly impaired. A longer treatment of 48h further improved the antifungal effect of F901318. Together, the results of this study indicate that F901318 initially has a fungistatic effect on Aspergillus spp. isolates by inhibiting germination and growth, but prolonged exposure is fungicidal through hyphal swelling followed by cell lysis.

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