Efficacy of olorofim (F901318) against Aspergillus fumigatus, A. nidulans , and A. tanneri in murine models of profound neutropenia and chronic granulomatous disease.

Emergence of azole-resistance in Aspergillus fumigatus as well as an increasing frequency of multi-resistant cryptic Aspergillus spp. necessitates exploration of new classes of antifungals. Olorofim (formerly F901318) is a new fungicidal agent that prevents growth of ascomycetous mold species via inhibition of de novo pyrimidine biosynthesis, a mechanism of action distinct from currently available antifungal drugs. We studied the in vivo efficacy of olorofim intraperitoneal therapy (15 mg/kg every 8 h for 9 days) against infection with A. fumigatus , A. nidulans, and A. tanneri in both neutropenic CD-1 mice and CGD mice (gp91phox-/- ). In the neutropenic model, 80% to 88% of treated mice survived and in the CGD group, 63% to 88% of treated mice survived for 10 days depending on the infecting species, while less than 10% of the mice in the contro l groups survived. In the olorofim-treated groups, galactomannan levels were significantly suppressed with lower organ fungal DNA burdens for all three Aspergillus spp. Histopathological slides revealed limited number of inflammatory foci with or without detectable fungal elements in the kidneys of neutropenic CD-1 mice and in the lungs of CGD mice. Furthermore, the efficacy of olorofim was unrelated to the triazole MICs of the infecting Aspergillus spp.. These results show olorofim to be a promising therapeutic agent for invasive aspergillosis.