Efficacy of Olorofim (F901318) Against , , and in Murine Models of Profound Neutropenia and Chronic Granulomatous Disease

The emergence of azole resistance in as well as an increasing frequency of multiresistant cryptic spp. necessitates exploration of new classes of antifungals. Olorofim (formerly F901318) is a new fungicidal agent that prevents the growth of ascomycetous mold species via inhibition of pyrimidine biosynthesis, a mechanism of action distinct from that of currently available antifungal drugs. We studied the efficacy of olorofim intraperitoneal therapy (15 mg/kg of body weight every 8 h for 9 days) against infection with , , and in both neutropenic CD-1 mice and mice with chronic granulomatous disease (CGD) ( mice). In the neutropenic mouse model, 80% to 88% of treated mice survived for 10 days, 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 control groups survived for 10 days. In the olorofim-treated groups, galactomannan levels were significantly suppressed, with lower organ fungal DNA burdens being seen for all three spp. Histopathological slides revealed a 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 spp. These results show olorofim to be a promising therapeutic agent for invasive aspergillosis.