title: 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 pathogenicAspergillusspp. 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 ofAspergillus fumigatusDHODH 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 ofA. fumigatussensitive 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.
authors: F2G Ltd., Manchester M30 0LX, United Kingdom; joliver@f2g.com.
authors: Jason D
authors: JD
authors: Oliver
authors: F2G Ltd., Manchester M30 0LX, United Kingdom.
authors: Graham E M
authors: GEM
authors: Sibley
authors: F2G Ltd., Manchester M30 0LX, United Kingdom.
authors: Nicola
authors: N
authors: Beckmann
authors: F2G Ltd., Manchester M30 0LX, United Kingdom.
authors: Katharine S
authors: KS
authors: Dobb
authors: Cresset, Litlington SG8 0SS, United Kingdom.
authors: Martin J
authors: MJ
authors: Slater
authors: Antimicrobial Pharmacodynamics and Therapeutics, Department of Molecular and Clinical Pharmacology, University of Liverpool, Liverpool L69 3GE, United Kingdom.
authors: Laura
authors: L
authors: McEntee
authors: F2G Ltd., Manchester M30 0LX, United Kingdom.
authors: Saskia
authors: S
authors: du Pré
authors: Antimicrobial Pharmacodynamics and Therapeutics, Department of Molecular and Clinical Pharmacology, University of Liverpool, Liverpool L69 3GE, United Kingdom.
authors: Joanne
authors: J
authors: Livermore
authors: F2G Ltd., Manchester M30 0LX, United Kingdom.
authors: Michael J
authors: MJ
authors: Bromley
authors: Fungus Testing Laboratory, Departments of Pathology and Medicine/Infectious Diseases, University of Texas Health Science Center at San Antonio, San Antonio, TX 78229.
authors: Nathan P
authors: NP
authors: Wiederhold
authors: Antimicrobial Pharmacodynamics and Therapeutics, Department of Molecular and Clinical Pharmacology, University of Liverpool, Liverpool L69 3GE, United Kingdom.
authors: William W
authors: WW
authors: Hope
authors: F2G Ltd., Manchester M30 0LX, United Kingdom.
authors: Anthony J
authors: AJ
authors: Kennedy
authors: F2G Ltd., Manchester M30 0LX, United Kingdom.
authors: Derek
authors: D
authors: Law
authors: F2G Ltd., Manchester M30 0LX, United Kingdom.
authors: Mike
authors: M
authors: Birch
keywords: Aspergillus fumigatus; antifungal drug; dihydroorotate dehydrogenase; mechanism of action