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Live Imaging of Antifungal Activity by Human Primary Neutrophils and Monocytes in Response to A. fumigatus
Published on: April 19, 2017
In vitro activity of the novel antifungal compound F901318 against difficult-to-treat Aspergillus isolates
J B Buil1,2, A J M M Rijs1,2, J F Meis1,2,3
1Department of Medical Microbiology, Radboud University Medical Centre, Nijmegen, The Netherlands.
Background:
F901318 is a new antifungal agent with a novel mechanism of action with activity against Aspergillus species. We investigated the in vitro activity of F901318 against a collection of Aspergillus isolates.
Methods:
A total of 213 Aspergillus isolates were used in this study. A total of 143 Aspergillus fumigatus sensu stricto isolates were used, of which 133 were azole resistant [25 TR34/L98H; 25 TR46/Y121F/T289A; 33 A. fumigatus with cyp51A-associated point mutations (25 G54, 1 G432 and 7 M220); and 50 azole-resistant A. fumigatus without known resistance mechanisms]. Ten azole-susceptible A. fumigatus isolates were used as WT controls. The in vitro activity was also determined against Aspergillus calidoustus (25 isolates), Aspergillus flavus (10), Aspergillus nidulans (10) and Aspergillus tubingensis (25). F901318 activity was compared with that of itraconazole, voriconazole, posaconazole, isavuconazole, amphotericin B and anidulafungin. Minimum effective concentrations and MICs were determined using the EUCAST broth microdilution method.
Results:
F901318 was active against all tested isolates: A. fumigatus WT, MIC90 0.125 mg/L (range 0.031-0.125); TR34/L98H,TR46/Y121F/T289A and azole resistant without known resistance mechanisms, MIC90 0.125 mg/L (range 0.031-0.25); A. fumigatus with cyp51A-associated point mutations, MIC90 0.062 mg/L (range 0.015-0.125); and other species, A. calidoustus MIC90 0.5 mg/L (range 0.125-0.5), A. flavus MIC90 0.062 mg/L (range 0.015-0.62), A. nidulans MIC90 0.125 mg/L (range 0.062-0.25) and A. tubingensis MIC90 0.062 mg/L (range 0.015-0.25).
Conclusions:
F901318 showed potent and consistent in vitro activity against difficult-to-treat Aspergillus spp. with intrinsic and acquired antifungal resistance due to known and unknown resistance mechanisms, suggesting no significant implications of azole resistance mechanisms for the mode of action of F901318.
Insights
The new antifungal agent F901318 demonstrates potent in vitro activity against Aspergillus species, including azole-resistant strains. This novel compound shows consistent efficacy, unaffected by common resistance mechanisms in Aspergillus.
Area of Science:
- Mycology
- Infectious Diseases
- Pharmacology
Background:
- F901318 is a novel antifungal agent targeting Aspergillus species.
- It possesses a unique mechanism of action distinct from existing antifungals.
Purpose of the Study:
- To evaluate the in vitro antifungal activity of F901318.
- To assess its efficacy against a diverse collection of Aspergillus isolates, including azole-resistant strains.
Main Methods:
- Tested 213 Aspergillus isolates, including various Aspergillus fumigatus strains with known azole resistance mechanisms (TR34/L98H, TR46/Y121F/T289A, cyp51A mutations) and other Aspergillus species.
- Determined Minimum Effective Concentrations (MECs) and Minimum Inhibitory Concentrations (MICs) using the EUCAST broth microdilution method.
- Compared F901318 activity against itraconazole, voriconazole, posaconazole, isavuconazole, amphotericin B, and anidulafungin.
Main Results:
- F901318 exhibited potent activity against all tested Aspergillus isolates, including wild-type and azole-resistant A. fumigatus.
- MIC90 values ranged from 0.062 to 0.125 mg/L for A. fumigatus strains and 0.062 to 0.5 mg/L for other Aspergillus species.
- Activity was consistent across different resistance mechanisms, with MIC90 values of 0.062 mg/L for A. fumigatus with cyp51A mutations.
Conclusions:
- F901318 demonstrates potent and consistent in vitro activity against challenging Aspergillus species.
- The agent is effective against isolates with intrinsic and acquired antifungal resistance.
- Azole resistance mechanisms do not appear to significantly impact the efficacy of F901318.
