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

Abstract

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), 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. 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 μg/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.

Fungal sensitization and positive fungal culture from sputum in children with asthma are associated with reduced lung function and acute asthma attacks respectively

“…45 More recently, PC1244 has shown activity against azole-resistant A fumigatus. 46 In addition, an early phase randomized controlled trial (RCT) of PUR1900, a dry powder itraconazole preparation has shown good safety and tolerability, higher lung and lower plasma concentration compared with oral treatment. 47 Identifying children who may benefit from these treatments for inclusion in clinical trials would be an important clinical advance.…”

“…The long‐acting inhaled azole PC945, a potent inhibitor of A fumigatus , may provide a targeted approach in the lung 45 . More recently, PC1244 has shown activity against azole‐resistant A fumigatus 46 . In addition, an early phase randomized controlled trial (RCT) of PUR1900, a dry powder itraconazole preparation has shown good safety and tolerability, higher lung and lower plasma concentration compared with oral treatment 47 .…”

Nikkomycin Z—Ready to Meet the Promise?

“…are the frequent focus of drug development. Recent reviews examine the available systemic antifungal drugs [ 7 , 12 , 13 , 14 , 15 , 16 ]. Thirteen new molecules include four in Phase 3 clinical trials [ 12 ].…”

Electrochemical and spectroscopic characterization of biologically important Schiff bases

“…1,2,4-triazoles are the subject of extensive investigations because of their various clinical, industrial, and agricultural applications. Triazoles are bestowed with extensive biological activities including antibacterial [17][18][19], anti-fungal [20], anti-viral [21][22], anti-cancer [23][24][25], anti-microbial, anti-tumour and cytotoxic activities [26][27]. Their biological applications are generally found to be related with their oxidation potential [28] that entails the transfer of a hydrogen atom through a proton coupled electron transfer reaction.…”