The effect of the novel antifungal drug F901318 (Olorofim) on the growth and viability of Aspergillus fumigatus

Saskia du Pré, Nicola Beckmann, Mariana Cruz Almeida, Graham E M Sibley, Derek Law, Alexandra C Brand, Mike Birch, Nick D Read, Jason D Oliver

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Abstract

F901318 (olorofim) is a novel antifungal drug that is highly active against Aspergillus species. Belonging to a new class of antifungals called the orotomides, F901318 targets dihydroorotate dehydrogenase (DHODH) in the de novo pyrimidine biosynthesis pathway. In this study, the antifungal effects of F901318 against Aspergillus fumigatus were investigated. Live-cell imaging revealed that, at a concentration of 0.1 μg/ml, F901318 completely inhibited germination, but conidia continued to expand by isotropic growth for >120 h. When this low F901318 concentration was applied to germlings or vegetative hyphae their elongation was completely inhibited within 10 h. Staining with the fluorescent viability dye bis-(1,3-dibutylbarbituric acid) trimethine oxonol (DiBAC) showed that prolonged exposure to F901318 (>24 h) led to vegetative hyphal swelling and a decrease in hyphal viability through cell lysis. The time-dependent killing of F901318 was further confirmed by measuring fungal biomass and growth rate in liquid culture. Compared to the untreated control, the ability of hyphal growth to recover in drug-free medium after 24h exposure to F901318 was strongly impaired. A longer treatment of 48h further improved the antifungal effect of F901318. Together, the results of this study indicate that F901318 initially has a fungistatic effect on Aspergillus spp. isolates by inhibiting germination and growth, but prolonged exposure is fungicidal through hyphal swelling followed by cell lysis.

Original languageEnglish
Article numbere00231-18
Pages (from-to)1-11
Number of pages11
JournalAntimicrobial Agents and Chemotherapy
Volume62
Issue number8
Early online date11 Jun 2018
DOIs
Publication statusPublished - 1 Aug 2018

Fingerprint

Aspergillus fumigatus
Aspergillus
Growth
Germination
Pharmaceutical Preparations
Fungal Spores
Hyphae
Fluorescent Dyes
Biomass
Cell Survival
Staining and Labeling
Acids

Keywords

  • Aspergillus fumigatus
  • F901318
  • antifungal agents
  • aspergillosis
  • filamentous fungi
  • olorofim
  • orotomide

Cite this

du Pré, S., Beckmann, N., Almeida, M. C., Sibley, G. E. M., Law, D., Brand, A. C., ... Oliver, J. D. (2018). The effect of the novel antifungal drug F901318 (Olorofim) on the growth and viability of Aspergillus fumigatus. Antimicrobial Agents and Chemotherapy, 62(8), 1-11. [e00231-18]. https://doi.org/10.1128/AAC.00231-18

The effect of the novel antifungal drug F901318 (Olorofim) on the growth and viability of Aspergillus fumigatus. / du Pré, Saskia; Beckmann, Nicola; Almeida, Mariana Cruz; Sibley, Graham E M; Law, Derek; Brand, Alexandra C; Birch, Mike; Read, Nick D; Oliver, Jason D.

In: Antimicrobial Agents and Chemotherapy, Vol. 62, No. 8, e00231-18, 01.08.2018, p. 1-11.

Research output: Contribution to journalArticle

du Pré, S, Beckmann, N, Almeida, MC, Sibley, GEM, Law, D, Brand, AC, Birch, M, Read, ND & Oliver, JD 2018, 'The effect of the novel antifungal drug F901318 (Olorofim) on the growth and viability of Aspergillus fumigatus', Antimicrobial Agents and Chemotherapy, vol. 62, no. 8, e00231-18, pp. 1-11. https://doi.org/10.1128/AAC.00231-18
du Pré, Saskia ; Beckmann, Nicola ; Almeida, Mariana Cruz ; Sibley, Graham E M ; Law, Derek ; Brand, Alexandra C ; Birch, Mike ; Read, Nick D ; Oliver, Jason D. / The effect of the novel antifungal drug F901318 (Olorofim) on the growth and viability of Aspergillus fumigatus. In: Antimicrobial Agents and Chemotherapy. 2018 ; Vol. 62, No. 8. pp. 1-11.
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AU - Brand, Alexandra C

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N1 - We thank our colleagues at F2G Ltd. for their support in this work, as well as the Manchester Fungal Infection Group at the University of Manchester. We also thank Gillian Milne and the Microscopy and Histology Core Facility at the Medical Research Council Centre for Medical Mycology at the University of Aberdeen for their assistance with TEM. We also thank John Rex for critical reading of the manuscript. The Microscopy and Histology Core Facility at the Medical Research Council Centre for Medical Mycology at the University of Aberdeen is supported by grant number MR/N006364/1. S.D.P. and M.C.A. are supported by the European Marie Curie ITN FungiBrain grant PITN-GA-2013-607963. S.D.P. was the primary author and performed the live-cell imaging microscopy, TEM, viability staining, and the analysis of the data. N.B. performed the postexposure effect assays. M.C.A. assisted with TEM. G.E.M.S. designed F901318. N.B., A.C.B., D.L., M.B., N.D.R., and J.D.O. provided guidance and assistance during this project and in the preparation of the manuscript.

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KW - Aspergillus fumigatus

KW - F901318

KW - antifungal agents

KW - aspergillosis

KW - filamentous fungi

KW - olorofim

KW - orotomide

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