Researchers based at the University of Liverpool (UK) and F2G Limited (Eccles, UK) have developed a novel antifungal compound, F901318, that could be utilized to treat invasive fungal infections such as aspergillosis.
Currently, there are relatively few treatments available to treat fungal infections, and emerging antifungal resistance and drug toxicity can make treatment challenging. F901318 represents the lead compound of a novel antifungal class termed ‘orotomides’ – the first new class of antifungals to be discovered in the last three decades. It's novel mechanism of action, inhibiting the fungal enzyme dihydroorotate dehydrogenase, has demonstrated potent activity against Aspergillus species.
Understanding the relationship between drug doses, the concentration of drug in the body and the antifungal effects is critical to progressing compounds for clinical use. The team, led by William Hope (University of Liverpool), therefore aimed to characterize the pharmacodynamics of this drug.
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F901318 was tested for end-point parameters including serum galactomannan, survival and histopathology in mouse and rabbit models, and it was benchmarked against a clinically relevant treatment. The researchers discovered that F901318 exhibits time-dependent antifungal activity and established pharmacodynamics targets such as the minimum inhibitory concentration. The team hope that these findings can now be used to select optimal drug regimens for Phase II and III clinical trials
Hope concluded: “Antifungal resistance represents a major global clinical challenge. This study provides the necessary information to enable F901318 to be developed for clinical use.”
Sources:Hope WW, McEntree L, Lovermore J et al. Pharmacodynamics of the Orotomides against Aspergillus fumigatus: New Opportunities for Treatment of Multidrug-Resistant Fungal Disease. mBio. 8(4) e01157–17. www.eurekalert.org/pub_releases/2017-10/uol-rhd100617.php