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

Jason D. Oliver, Graham E.M. Sibley, Nicola Beckmann, Katharine S. Dobb, Martin J. Slater, Laura McEntee, Saskia Du Pré, Joanne Livermore, Michael J. Bromley, Nathan P. Wiederhold, William W. Hope, Anthony J. Kennedy, Derek Law, Mike Birch

Research output: Contribution to journalArticle

61 Scopus citations

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/mL-greater 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.

Original languageEnglish (US)
Pages (from-to)12809-12814
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume113
Issue number45
DOIs
StatePublished - Nov 8 2016

Keywords

  • Antifungal drug
  • Aspergillus fumigatus
  • Dihydroorotate dehydrogenase
  • Mechanism of action

ASJC Scopus subject areas

  • General

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    Oliver, J. D., Sibley, G. E. M., Beckmann, N., Dobb, K. S., Slater, M. J., McEntee, L., Du Pré, S., Livermore, J., Bromley, M. J., Wiederhold, N. P., Hope, W. W., Kennedy, A. J., Law, D., & Birch, M. (2016). F901318 represents a novel class of antifungal drug that inhibits dihydroorotate dehydrogenase. Proceedings of the National Academy of Sciences of the United States of America, 113(45), 12809-12814. https://doi.org/10.1073/pnas.1608304113