Olorofim activity against multidrug-resistant Fusarium unveils intra-species and inter-species variability.

Abstract

Fungi in the genus Fusarium are plant pathogens but are also capable of causing a wide range of diseases in humans. The intrinsic multi-drug resistance of Fusarium often leads to a poor clinical outcome in patients with severe immune disorders. Olorofim, a member of the orotomide class, is a novel type of antifungal drug that interferes with pyrimidine biosynthesis by inhibiting dihydroorotate dehydrogenase and thereby prevents growth and cell division. In this study, the in vitro activity of olorofim was evaluated against 253 Fusarium isolates, of which 228 isolates belonging to the prevalent complexes involved in human infection, F. solani species complex (SC) and F. fujikuroi SC. All Fusarium isolates underwent species-level identification via multi-locus sequence typing (MLST) targeting RPB1, RPB2, and TEF1 loci. Antifungal susceptibility testing was performed using a CLSI M38, 3rd ed. broth microdilution for olorofim. The geometric mean of the MICs of olorofim for all 253 isolates was 0.581 µg/mL, ranging from 0.015 µg/mL to >16 µg/mL. Olorofim demonstrated high MICs against F. solani SC, whereas greater potency (lower MICs) was observed against F. fujikuroi SC. Clinical isolates tended to have higher MIC values than environmental isolates, but this pattern was not consistent across all species complexes. Overall, olorofim demonstrated moderate in vitro activity against Fusarium isolates, suggesting it might be a potential candidate for treating fusarioses caused by multidrug-resistant strains.