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Published on: December 28, 2017
Olorofim activity against multidrug-resistant Fusarium unveils intra-species and inter-species variability
Ruoning Xue1,2,3, Shenghan Gao4, Sybren de Hoog2,5,6,7
1Department of Dermatology and Venerology, Peking University First Hospital, Beijing, China.
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.
Insights
Olorofim shows moderate in vitro activity against Fusarium species, including drug-resistant strains. This novel antifungal may offer a new treatment option for invasive fusariosis infections.
Area of Science:
- Mycology
- Infectious Diseases
- Pharmacology
Background:
- * Fusarium* species are significant plant pathogens and opportunistic human pathogens.
- * Fusarium* infections (fusarioses) are challenging to treat due to intrinsic multi-drug resistance.
- Severe immune compromise increases susceptibility to invasive fusarioses.
Purpose of the Study:
- To evaluate the in vitro antifungal activity of olorofim against clinical and environmental *Fusarium* isolates.
- To determine the minimum inhibitory concentrations (MICs) of olorofim for *Fusarium* species complexes implicated in human infections.
- To assess olorofim's potential as a treatment for multidrug-resistant fusarioses.
Main Methods:
- Species-level identification of 253 *Fusarium* isolates using multi-locus sequence typing (MLST) of *RPB1*, *RPB2*, and *TEF1* genes.
- Antifungal susceptibility testing performed via CLSI M38 broth microdilution method.
- Geometric mean MICs calculated to assess overall antifungal activity.
Main Results:
- Olorofim exhibited a geometric mean MIC of 0.581 µg/mL against 253 *Fusarium* isolates.
- Higher MICs were observed for *F. solani* species complex (SC) compared to *F. fujikuroi* SC.
- Clinical isolates generally showed higher MICs than environmental isolates, though not consistently across all species complexes.
Conclusions:
- Olorofim demonstrates moderate in vitro activity against a broad range of *Fusarium* species.
- The drug shows differential potency, with greater activity against *F. fujikuroi* SC.
- Olorofim represents a potential therapeutic candidate for treating invasive fusarioses, particularly those caused by multidrug-resistant strains.
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