The novel antifungal compound F901318 has potent in vitro and in vivo activity against Aspergillus terreus, including cryptic species

U Binder1, M Lackner1, D Grässle1, V Naschberger1, N Beckmann2, P Warn3, J Gold3, D Law2, M Birch2, C Lass-Flörl1

Author address: 

1Division of Hygiene and Medical Microbiology, Medical University Innsbruck, Austria 2F2G Limited, Manchester, UK 3Evotec Ltd, Oxfordshire, UK

Abstract: 

Purpose: Among invasive infections caused by aspergilli, members of the Aspergillus terreus species complex hold an exceptional position. First, because they appear to be rarely seen in the clinics compared to infections with A. fumigatus and second, because they display resistance to amphotericin B. Here, we assessed the activity of the dihydroorotate dehydrogenase inhibitor F901318 against a collection of A. terreus sensu stricto and cryptic species.

Methods: The in vitro potency of F901318 was evaluated against a total of 93 A. terreus clinical isolates by using CLSI M38-A2 method and testing concentrations from 0.0005 – 16 mg/L. Fourty-two of the isolates were determined to be A. terreus sensu stricto and 51 belonged to cryptic species, which included A. alabamensis (n = 8), A. citrinoterreus (n = 27), A. floccosus (n = 1), A. hortai (n = 13) and A. neoafricanus (n = 1). F901318 activity was compared with that of common antifungal agents. In vivo efficacy of F901318 was determined in a murine model of disseminated aspergillosis by assessing disease progression in mice infected with an A. terreus sensu stricto isolate.

Results: F901318 was highly active against all tested A. terreus strains, exhibiting MICs in a range of 0.0078-0.0313 mg/L. MICs obtained for F901318 were significantly lower than those observed for the azoles. Even selected strains that showed azole resistance, were highly sensitive to F901318. Furthermore, survival of mice infected with A. terreus and treated with F901318 dosed by both the IV and oral routes was increased significantly compared to the control group. F901318 treated mice showed 100% survival at day 10 post infection, while 90% mice in the control group were dead at this timepoint.

Conclusion: F901318 showed potent and consistent in vitro activity against all A. terreus strains tested, inlcuding those with elevated MICs to other antifungal substances. Overall, growth inhibition was obvious at lower concentration of F901318 compared to other antifungal drugs. Furthermore, in vivo data showed that F901318 was highly efficacious in prolonging survival of mice with disseminated aspergillosis due to A. terreus.

2018

Full conference title: 

The 8th Advances Against Aspergillus, Lisbon Conference Center, Lisbon, Portugal
    • AAA 8th (2018)