Anti-fungal activity of a novel triazole, PC1244, against emerging azole-resistant Aspergillus fumigatus and other species of Aspergillus

Thomas Colley, Cheshta Sharma, Alexandre Alanio, Genki Kimura, Leah Daly, Takahiro Nakaoki, Yuki Nishimoto, Stéphane Bretagne, Yasuo Kizawa, Pete Strong, Garth Rapeport, Kazuhiro Ito, Jacques F. Meis, Anuradha Chowdhary

研究成果: ジャーナルへの寄稿記事査読

11 被引用数 (Scopus)

抄録

Objectives: 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. Methods: 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), TR46 3/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. Results: 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 lg/mouse) to the A. fumigatus (AF91 with M220V)-infected mice reduced pulmonary fungal load and serum galactomannan more than intranasal posaconazole. Conclusions: PC1244 has the potential to become a novel topical treatment of azole-resistant pulmonary aspergillosis.

本文言語英語
ページ(範囲)2950-2958
ページ数9
ジャーナルJournal of Antimicrobial Chemotherapy
74
10
DOI
出版ステータス出版済み - 1 10月 2019

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