F901318 represents a novel class of antifungal drug that inhibits dihydroorotate dehydrogenase
Open accessAbstract
Significance: New antifungal drugs that act via novel mechanisms are urgently needed to combat the high mortality of invasive fungal disease and the emergence of resistance to existing therapies. We describe the discovery, structure, activity, and mechanism of action of F901318, a new antifungal agent. A member of a novel class of antifungals, the orotomides, F901318 acts via inhibition of dihydroorotate dehydrogenase, an enzyme of de novo pyrimidine biosynthesis. F901318 is currently in clinical development for the treatment of invasive aspergillosis.
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
F90138 is highly effective against most Aspergillus species, with a MIC of <0.1 μg/mL.
“This compound is highly effective against most Aspergillus species, with a MIC of <0.1 μg/mL (40).”
From Recent Progress in Research on Mitochondrion-Targeted Antifungal Drugs: a Review (2023) · cites this paper as [40]
The Discovery of F901318 section reports MICs below 0.1 μg/mL for multiple strains of four Aspergillus species, supporting the potency and MIC claims. It does not establish that this applies to most Aspergillus species. The cited compound is F901318; “F90138” appears to be a typo. (LLM, conf=0.83)
Experimental — accuracy not yet measuredF90138 targets DHODH, an essential mitochondrial enzyme that catalyzes the conversion of dihydroorotate to orotate in the de novo pyrimidine biosynthesis pathway.
“F90138 targets DHODH, an essential mitochondrial enzyme that catalyzes the conversion of dihydroorotate to orotate in the de novo pyrimidine biosynthesis pathway (40).”
From Recent Progress in Research on Mitochondrion-Targeted Antifungal Drugs: a Review (2023) · cites this paper as [40]
The “DHODH Is the Target of F901318” section (page not provided) confirms that F901318 targets DHODH and that DHODH converts dihydroorotate to orotate in pyrimidine biosynthesis. The discussion describes DHODH as a key enzyme in the de novo pathway, and the structural section links it to the inner mitochondrial membrane. The citing sentence instead names the compound F90138; our copy identifies it as F901318 and does not directly call DHODH an essential enzyme. (LLM, conf=0.87)
Experimental — accuracy not yet measuredThe selectivity of F90138 is more than 2,200-fold higher for A. fumigatus DHODH than against the mammalian enzyme.
“The selectivity of F90138 is more than 2,200-fold higher A. fumigatus DHODH than against the mammalian enzyme, which indicates that F90138 is a potential inhibitor that binds to fungal DHODH.”
From Recent Progress in Research on Mitochondrion-Targeted Antifungal Drugs: a Review (2023) · cites this paper as [40]
Olorofim is a first-in-class orotomide that affects pyrimidine synthesis via reversible inhibition of dihydroorotate dehydrogenase.
“Olorofim, developed by F2G, is a first-in-class orotomide which affects pyrimidine synthesis via reversible inhibition of dihydroorotate dehydrogenase (DHODH) [63].”
From Investigational Agents for the Treatment of Resistant Yeasts and Molds (2021) · cites this paper as [63]
Olorofim lacks activity against Mucorales species and Exophiala dermatitidis due to phylogenetically different DHODH target enzymes.
“It is important to note this drug lacks activity against Mucorales species or Exophiala dermatitidis due to phylogenetically different DHODH target enzymes [63, 65].”
From Investigational Agents for the Treatment of Resistant Yeasts and Molds (2021) · cites this paper as [63]
Fosmanogepix and olorofim are the first drugs in their respective classes.
“Perhaps the brightest future for the future of invasive mold infections lie in stage II and I agents fosmanogepix and olorofim, both first agents in their respective classes.”
From Investigational Agents for the Treatment of Resistant Yeasts and Molds (2021) · cites this paper as [63]
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Cites
Phylogeny.fr: robust phylogenetic analysis for the non-specialist
Dereeper, A., Guignon, V., Blanc, G., Audic, S., Buffet, S., Chevenet, F., Dufayard, J.-F., Guindon, S., Lefort, V., Lescot, M., et al. (2008) · Nucleic Acids Research · doi:10.1093/nar/gkn180 · Cited by 4,700 · see citing works
Hidden Killers: Human Fungal Infections
Brown, G. D., Denning, D. W., Gow, N. A. R., Levitz, S. M., Netea, M. G., & White, T. C. (2012) · Science Translational Medicine · doi:10.1126/scitranslmed.3004404 · Cited by 4,284 · see citing works
Drugs for bad bugs: confronting the challenges of antibacterial discovery
Payne, D. J., Gwynn, M. N., Holmes, D. J., & Pompliano, D. L. (2007) · Nature Reviews Drug Discovery · doi:10.1038/nrd2201 · Cited by 2,512 · see citing works
How were new medicines discovered?
Swinney, D. C., & Anthony, J. (2011) · Nature Reviews Drug Discovery · doi:10.1038/nrd3480 · Cited by 1,812 · see citing works
Antifungal Drug Development: Challenges, Unmet Clinical Needs, and New Approaches
Roemer, T., & Krysan, D. J. (2014) · Cold Spring Harbor Perspectives in Medicine · doi:10.1101/cshperspect.a019703 · Cited by 593 · see citing works
Noble, S. M., & Johnson, A. D. (2005) · Eukaryotic Cell · doi:10.1128/ec.4.2.298-309.2005 · Cited by 592 · see citing works
Verweij, P. E., Chowdhary, A., Melchers, W. J. G., & Meis, J. F. (2016) · Clinical Infectious Diseases · doi:10.1093/cid/civ885 · Cited by 561 · see citing works
Denning, D. W., Pleuvry, A., & Cole, D. C. (2013) · Medical Mycology · doi:10.3109/13693786.2012.738312 · Cited by 495 · see citing works
How to bolster the antifungal pipeline
Denning, D. W., & Bromley, M. (2015) · Science · doi:10.1126/science.aaa6097 · Cited by 481 · see citing works
Self-citationGlobal burden of chronic pulmonary aspergillosis as a sequel to pulmonary tuberculosis
Denning, D., Pleuvry, A., & Cole, D. (2011) · Bulletin of the World Health Organization · doi:10.2471/blt.11.089441 · Cited by 420 · cited 5× · see citing works
“UDP-glucose for β-(1,3)-glucan synthesis.”
BackgroundInfluentialChowdhary, A., Kathuria, S., Xu, J., & Meis, J. F. G. M. (2013) · PLoS Pathogens · doi:10.1371/journal.ppat.1003633 · Cited by 383 · see citing works
Phillips, M. A., Lotharius, J., Marsh, K. C., White, J. C., Dayan, A. D., White, K. L., Njoroge, J. W., Mazouni, F. E., Lao, Y., Kokkonda, S., et al. (2015) · Science Translational Medicine · doi:10.1126/scitranslmed.aaa6645 · Cited by 383 · see citing works
Teriflunomide and Its Mechanism of Action in Multiple Sclerosis
Bar‐Or, A., Pachner, A. R., Menguy-Vacheron, F., Kaplan, J. M., & Wiendl, H. (2014) · Drugs · doi:10.1007/s40265-014-0212-x · Cited by 366 · see citing works
Nett, J. E., & Andes, D. R. (2016) · Infectious Disease Clinics of North America · doi:10.1016/j.idc.2015.10.012 · Cited by 351 · see citing works
Structures of human dihydroorotate dehydrogenase in complex with antiproliferative agents
Liu, S., Neidhardt, E. A., Grossman, T. H., Ocain, T., & Clardy, J. (2000) · Structure · doi:10.1016/s0969-2126(00)00077-0 · Cited by 347 · see citing works
Therapy for fungal diseases: opportunities and priorities
Denning, D. W., & Hope, W. W. (2010) · Trends in Microbiology · doi:10.1016/j.tim.2010.02.004 · Cited by 314 · see citing works
Self-citationBrand, A., MacCallum, D. M., Brown, A. J. P., Gow, N. A. R., & Odds, F. C. (2004) · Eukaryotic Cell · doi:10.1128/ec.3.4.900-909.2004 · Cited by 272 · see citing works
On Dihydroorotate Dehydrogenases and Their Inhibitors and Uses
Munier-Lehmann, H., Vidalain, P.-O., Tangy, F., & Janin, Y. L. (2013) · Journal of Medicinal Chemistry · doi:10.1021/jm301848w · Cited by 209 · see citing works
Epidemiology and molecular mechanisms of antifungal resistance in Candida and Aspergillus
Gonçalves, S. S., Souza, A. C. R., Chowdhary, A., Meis, J. F. G. M., & Colombo, A. L. (2016) · Mycoses · doi:10.1111/myc.12469 · Cited by 182 · see citing works
Triazole Resistance in Aspergillus spp.: A Worldwide Problem?
Rivero-Menendez, O., Alastruey-Izquierdo, A., Mellado, E., & Cuenca-Estrella, M. (2016) · Journal of Fungi · doi:10.3390/jof2030021 · Cited by 142 · see citing works
Vyas, V. K., & Ghate, M. D. (2011) · Mini-Reviews in Medicinal Chemistry · doi:10.2174/138955711797247707 · Cited by 137 · see citing works
Requirements for the mitochondrial import and localization of dihydroorotate dehydrogenase
Rawls, J. M., Knecht, W., Diekert, K., Lill, R., & Löffler, M. (2000) · European Journal of Biochemistry · doi:10.1046/j.1432-1327.2000.01213.x · Cited by 131 · see citing works
Attenuated virulence of uridine-uracil auxotrophs of Aspergillus fumigatus
D'Enfert, C., Diaquin, M., Delit, A., Wuscher, N., Debeaupuis, J. P., Huerre, M., & Latge, J. P. (1996) · Infection and Immunity · doi:10.1128/iai.64.10.4401-4405.1996 · Cited by 123 · see citing works
Osherov, N. (2001) · Journal of Antimicrobial Chemotherapy · doi:10.1093/jac/48.1.75 · Cited by 96 · see citing works
Azole resistance in allergic bronchopulmonary aspergillosis and Aspergillus bronchitis
Howard, S. J., Pasqualotto, A. C., & Denning, D. W. (2009) · Clinical Microbiology and Infection · doi:10.1111/j.1469-0691.2009.02911.x · Cited by 85 · see citing works
Goldstein, A. L., & McCusker, J. H. (2001) · Genetics · doi:10.1093/genetics/159.2.499 · Cited by 75 · see citing works
Overview of treatment options for invasive fungal infections
Pound, M. W., Townsend, M. L., DiMondi, V. P., Wilson, D. T., & Drew, R. H. (2011) · Medical Mycology · doi:10.3109/13693786.2011.560197 · Cited by 69 · see citing works
Copeland, R. A., Davis, J. P., Dowling, R. L., Lombardo, D., Murphy, K., & Patterson, T. A. (1995) · Archives of Biochemistry and Biophysics · doi:10.1006/abbi.1995.0012 · Cited by 62 · see citing works
Liu, W. Y., May, G. S., Lionakis, M. S., Lewis, R. E., & Kontoyiannis, D. P. (2004) · Antimicrobial Agents and Chemotherapy · doi:10.1128/aac.48.7.2490-2496.2004 · Cited by 55 · see citing works
TheURA5Gene Is Necessary forHistoplasma capsulatumGrowth during Infection of Mouse and Human Cells
Retallack, D. M., Heinecke, E. L., Gibbons, R. S., et al. (1999) · Infection and Immunity · doi:10.1128/iai.67.2.624-629.1999 · Cited by 51 · see citing works
Zameitat, E., Gojković, Z., Knecht, W., Piškur, J., & Löffler, M. (2006) · FEBS Journal · doi:10.1111/j.1742-4658.2006.05327.x · Cited by 33 · see citing works
Gontijo, F. D. A., Pascon, R. C., Fernandes, L., Machado, J., Alspaugh, J. A., & Vallim, M. A. (2014) · Fungal Genetics and Biology · doi:10.1016/j.fgb.2014.06.003 · Cited by 29 · see citing works
Serum `uracil + uridine' levels in normal subjects and their possible significance
Parry, T. E., & Blackmore, J. A. (1974) · Journal of Clinical Pathology · doi:10.1136/jcp.27.10.789 · Cited by 12 · see citing works
Flagged first, then by citations
Research works printed but not linked: 1
- Retallack DM, Heinecke EL, Gibbons R, Deepe GS, Jr, Woods JP (1999) The URA5 gene is necessary for Histoplasma capsulatum growth during infection of mouse and hu- man cells. Infect Immun 67(2):624-629.
Cited by
Sorted by citations
The antifungal pipeline: a reality check
Perfect, J. R. (2017) · Nature Reviews Drug Discovery · doi:10.1038/nrd.2017.46 · Cited by 866 · see citing works
Campoy, S., & Adrio, J. L. (2017) · Biochemical Pharmacology · doi:10.1016/j.bcp.2016.11.019 · Cited by 511 · see citing works
The Antifungal Pipeline: Fosmanogepix, Ibrexafungerp, Olorofim, Opelconazole, and Rezafungin
Hoenigl, M., Sprute, R., Egger, M., Arastehfar, A., Cornely, O. A., Krause, R., Lass-Flörl, C., Prattes, J., Spec, A., Thompson, G. R., et al. (2021) · Drugs · doi:10.1007/s40265-021-01611-0 · Cited by 467 · see citing works
Self-citationScedosporium and Lomentospora: an updated overview of underrated opportunists
Ramirez-Garcia, A., Pellon, A., Rementeria, A., Buldain, I., Barreto-Bergter, E., Rollin-Pinheiro, R., de Meirelles, J. V., Xisto, M. I. D. S., Ranque, S., Havlicek, V., et al. (2018) · Medical Mycology · doi:10.1093/mmy/myx113 · Cited by 264 · see citing works
The antifungal arsenal: alternative drugs and future targets
Wiederhold, N. P. (2018) · International Journal of Antimicrobial Agents · doi:10.1016/j.ijantimicag.2017.09.002 · Cited by 149 · see citing works
Self-citationThe Future of Antifungal Drug Therapy: Novel Compounds and Targets
Mota Fernandes, C., Dasilva, D., Haranahalli, K., McCarthy, J. B., Mallamo, J., Ojima, I., & Del Poeta, M. (2021) · Antimicrobial Agents and Chemotherapy · doi:10.1128/aac.01719-20 · Cited by 124 · see citing works
Development and research progress of anti-drug resistant fungal drugs
Cui, X., Wang, L., Lü, Y., & Yue, C. (2022) · Journal of Infection and Public Health · doi:10.1016/j.jiph.2022.08.004 · Cited by 85 · see citing works
Wiederhold, N. P., Najvar, L. K., Jaramillo, R., Olivo, M., Birch, M., Law, D., Rex, J. H., Catano, G., & Patterson, T. F. (2018) · Antimicrobial Agents and Chemotherapy · doi:10.1128/aac.00999-18 · Cited by 80 · see citing works
Self-citationVerma, S., Shakya, V. P. S., & Idnurm, A. (2018) · Virulence · doi:10.1080/21505594.2017.1414133 · Cited by 67 · see citing works
Rivero-Menendez, O., Cuenca-Estrella, M., & Alastruey-Izquierdo, A. (2019) · Journal of Antimicrobial Chemotherapy · doi:10.1093/jac/dkz078 · Cited by 66 · see citing works
Seyedmousavi, S., Chang, Y. C., Law, D., Birch, M., Rex, J. H., & Kwon-Chung, K. J. (2019) · Antimicrobial Agents and Chemotherapy · doi:10.1128/aac.00129-19 · Cited by 56 · see citing works
Self-citationAl-Hatmi, A., de Hoog, G. S., & Meis, J. F. (2019) · Infection and Drug Resistance · doi:10.2147/idr.s180912 · Cited by 47 · see citing works
Antifungals in Clinical Use and the Pipeline
Johnson, M. D. (2021) · Infectious Disease Clinics of North America · doi:10.1016/j.idc.2021.03.005 · Cited by 35 · see citing works
Recent Progress in Research on Mitochondrion-Targeted Antifungal Drugs: a Review
Qin, Y., Wang, J., Lv, Q., & Han, B. (2023) · Antimicrobial Agents and Chemotherapy · doi:10.1128/aac.00003-23 · Cited by 38 · see citing works
“F90138 targets DHODH, an essential mitochondrial enzyme that catalyzes the conversion of dihydroorotate to orotate in the de novo pyrimidine biosynthesis pathway (40).”
BackgroundInvestigational Agents for the Treatment of Resistant Yeasts and Molds
Seiler, G. T., & Ostrosky-Zeichner, L. (2021) · Current Fungal Infection Reports · doi:10.1007/s12281-021-00419-5 · Cited by 32 · see citing works
She, X., Zhang, L., Peng, J., Zhang, J., Li, H., Zhang, P., Calderone, R., Liu, W., & Li, D. (2020) · Frontiers in Microbiology · doi:10.3389/fmicb.2020.559975 · Cited by 16 · see citing works
How do I manage refractory invasive pulmonary aspergillosis
Vergidis, P., Sendi, P., Alkhateeb, H. B., & Nguyen, M. H. (2024) · Clinical Microbiology and Infection · doi:10.1016/j.cmi.2024.01.015 · Cited by 12 · see citing works
Special considerations for the diagnosis and treatment of invasive pulmonary aspergillosis
McCarthy, M. W., & Walsh, T. J. (2017) · Expert Review of Respiratory Medicine · doi:10.1080/17476348.2017.1340835 · Cited by 8 · see citing works
- Authors
- 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.
- Affiliations
- F2G (United Kingdom) (GB)
- Cresset (United Kingdom) (GB)
- University of Liverpool (GB)
- F2G Ltd., Manchester M30 0LX, United Kingdom;
- Government of the United States of America (US)
- The University of Texas at San Antonio Health Science Center (US)
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 2016-10-25
- Volume
- 113
- Issue
- 45
- Pages
- 12809-12814
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC5111691
- OpenAlex
- W2532067600
- Cited by
- 289
- References
- 33
- Citations by year
- 2026: 31 · 2025: 43 · 2024: 33 · 2023: 37 · 2022: 27 · 2021: 39 · 2020: 28 · 2019: 16 · 2018: 18 · 2017: 16 · 2016: 1
- FWCI
- 15.70
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Research Explorer (The University of Manchester) (submittedVersion, other-oa)
- Funders
- European Commission (607963)
- Topics
- Health Sciences › Medicine › Infectious Diseases › Antifungal resistance and susceptibility
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Biochemical and Molecular Research
- Physical Sciences › Chemistry › Organic Chemistry › Synthesis and Characterization of Heterocyclic Compounds
- Keywords
- antifungal agents, dihydroorotate dehydrogenase inhibition, de novo pyrimidine biosynthesis, invasive aspergillosis, fungal drug resistance, structure-activity relationship, mechanism of action
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
