F901318 represents a novel class of antifungal drug that inhibits dihydroorotate dehydrogenase

Abstract

There is an important medical need for new antifungal agents with novel mechanisms of action to treat the increasing number of patients with life-threatening systemic fungal disease and to overcome the growing problem of resistance to current therapies. F901318, the leading representative of a novel class of drug, the orotomides, is an antifungal drug in clinical development that demonstrates excellent potency against a broad range of dimorphic and filamentous fungi. In vitro susceptibility testing of F901318 against more than 100 strains from the four main pathogenic Aspergillus spp. revealed minimal inhibitory concentrations of ≤0.06 μg/mLgreater potency than the leading antifungal classes. An investigation into the mechanism of action of F901318 found that it acts via inhibition of the pyrimidine biosynthesis enzyme dihydroorotate dehydrogenase (DHODH) in a fungal-specific manner. Homology modeling of Aspergillus fumigatus DHODH has identified a predicted binding mode of the inhibitor and important interacting amino acid residues. In a murine pulmonary model of aspergillosis, F901318 displays in vivo efficacy against a strain of A. fumigatus sensitive to the azole class of antifungals and a strain displaying an azole-resistant phenotype. F901318 is currently in late Phase 1 clinical trials, offering hope that the antifungal armamentarium can be expanded to include a class of agent with a mechanism of action distinct from currently marketed antifungals.antifungal drug | Aspergillus fumigatus | mechanism of action | dihydroorotate dehydrogenase

The antifungal pipeline: a reality check

“…It is currently in phase II development as an intravenous and oral agent for use in systemic mould infections, with a particular emphasis on aspergillosis and scedosporiosis (NCT02856178) 8 . The mechanism of action is very well described.…”

“…It is a potent inhibitor of Aspergillus spp. dihydroorotate dehydrogenase, which is crucially involved in fungal pyrimidine biosynthesis 8 . Humans also have this enzyme, but F901318 is a 2,000-fold more potent inhibitor of the fungal enzyme than the mammalian enzyme homologue and, with this differential inhibitory activity, its toxicity towards mammalian cells is anticipated to be very low 8 .…”

“…dihydroorotate dehydrogenase, which is crucially involved in fungal pyrimidine biosynthesis 8 . Humans also have this enzyme, but F901318 is a 2,000-fold more potent inhibitor of the fungal enzyme than the mammalian enzyme homologue and, with this differential inhibitory activity, its toxicity towards mammalian cells is anticipated to be very low 8 . A similar phenomenon had previously been observed with an antibacterial compound, trimethoprim, which inhibits dihydrofolate reductase in both bacteria and humans with substantially different kinetics.…”

“…A similar phenomenon had previously been observed with an antibacterial compound, trimethoprim, which inhibits dihydrofolate reductase in both bacteria and humans with substantially different kinetics. F901318 has potent anti- Aspergillus activity in treatment of animal models 8 . Although it has poor activity against yeasts in vitro , it does possess fungicidal activity against a series of moulds and most endemic (dimorphic) mycoses 8 .…”

“…These biomarkers enable invasive mycoses to be controlled at the early stages of infection when the tissue burden of fungi is low, an important feature of effective fungal control. Third, there has been a collation of both objective and subjective opinions into a series of antifungal management guidelines 3–8 , so that health-care systems and clinicians have basic standards to help initiate and compare successful treatments and strategies. Last, the most important factor for the successful management of fungal infections is the continued development and appropriate use of both new and old antifungal drugs.…”