Anti-fungal activity of a novel triazole, PC1244, against emerging azole-resistant Aspergillus fumigatus and other species of Aspergillus.
Animals
Antifungal Agents
/ pharmacology
Aspergillus
/ classification
Colony Count, Microbial
Disease Models, Animal
France
Galactose
/ analogs & derivatives
Humans
India
Lung
/ microbiology
Mannans
/ blood
Mice
Microbial Sensitivity Tests
Netherlands
Pulmonary Aspergillosis
/ microbiology
Treatment Outcome
Triazoles
/ administration & dosage
Journal
The Journal of antimicrobial chemotherapy
ISSN: 1460-2091
Titre abrégé: J Antimicrob Chemother
Pays: England
ID NLM: 7513617
Informations de publication
Date de publication:
01 10 2019
01 10 2019
Historique:
received:
25
02
2019
revised:
10
05
2019
accepted:
14
06
2019
pubmed:
31
7
2019
medline:
16
7
2020
entrez:
31
7
2019
Statut:
ppublish
Résumé
The growing emergence of azole-resistant Aspergillus fumigatus strains worldwide is a major concern for current systemic antifungal treatment. Here we report antifungal activities of a novel inhaled triazole, PC1244, against a collection of multi-azole-resistant A. fumigatus strains. MICs of PC1244 were determined for A. fumigatus carrying TR34/L98H (n = 81), TR46/Y121F/T289A (n = 24), M220 (n = 6), G54 (n = 11), TR53 (n = 1), TR463/Y121F/T289A (n = 2), G448S (n = 1), G432C (n = 1) and P216S (n = 1) resistance alleles originating from either India, the Netherlands or France. The effects of PC1244 were confirmed in an in vitro model of the human alveolus and in vivo in temporarily neutropenic, immunocompromised mice. PC1244 exhibited potent inhibition [geometric mean MIC (range), 1.0 mg/L (0.125 to >8 mg/L)] of growth of A. fumigatus strains carrying cyp51A gene mutations, showing much greater potency than voriconazole [15 mg/L (0.5 to >16 mg/L)], and an effect similar to those on other azole-susceptible Aspergillus spp. (Aspergillus flavus, Aspergillus terreus, Aspergillus tubingensis, Aspergillus nidulans, Aspergillus niger, Aspergillus nomius, Aspergillus tamarii) (0.18-1 mg/L). In TR34/L98H and TR46/Y121F/T289A A. fumigatus-infected in vitro human alveolus models, PC1244 achieved superior inhibition (IC50, 0.25 and 0.34 mg/L, respectively) compared with that of voriconazole (IC90, >3 mg/L and >10 mg/L, respectively). In vivo, once-daily intranasal administration of PC1244 (0.56-70 μg/mouse) to the A. fumigatus (AF91 with M220V)-infected mice reduced pulmonary fungal load and serum galactomannan more than intranasal posaconazole. PC1244 has the potential to become a novel topical treatment of azole-resistant pulmonary aspergillosis.
Identifiants
pubmed: 31361006
pii: 5540742
doi: 10.1093/jac/dkz302
pmc: PMC6753496
doi:
Substances chimiques
Antifungal Agents
0
Mannans
0
Triazoles
0
galactomannan
11078-30-1
Galactose
X2RN3Q8DNE
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
2950-2958Informations de copyright
© The Author(s) 2019. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy.
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