Pulmocide Ltd, London, UK.
Department of Medical Mycology, Vallabhbhai Patel Chest Institute, University of Delhi, Delhi, India.
J Antimicrob Chemother. 2019 Oct 1;74(10):2950-2958. doi: 10.1093/jac/dkz302.
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.
曲霉菌中唑类耐药菌株的不断出现，是当前全身抗真菌治疗的主要关注点。本研究报告了一种新型吸入性三唑类化合物 PC1244 对多种唑类耐药烟曲霉菌株的抗真菌活性。
测定了携带 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）和 P216S（n=1）耐药等位基因的烟曲霉对 PC1244 的 MIC 值，这些耐药等位基因均来自印度、荷兰或法国。在体外人肺泡模型和暂时中性粒细胞减少、免疫功能低下的小鼠体内模型中，对 PC1244 的作用进行了验证。
PC1244 对携带 cyp51A 基因突变的烟曲霉菌株表现出强大的抑制生长作用[几何均数 MIC（范围），1.0mg/L（0.125 至>8mg/L）]，其效力明显优于伏立康唑[15mg/L（0.5 至>16mg/L）]，与其他唑类敏感的曲霉菌属（黄曲霉、土曲霉、构巢曲霉、米曲霉、黑曲霉、棒曲霉、拟青霉）的作用相似（0.18-1mg/L）。在 TR34/L98H 和 TR46/Y121F/T289A 烟曲霉感染的体外人肺泡模型中，PC1244 的抑制作用优于伏立康唑（IC50 分别为 0.25 和 0.34mg/L）。在体内，烟曲霉（AF91 携带 M220V）感染小鼠中，每日一次经鼻给予 PC1244（0.56-70μg/只），可降低肺部真菌负荷和血清半乳甘露聚糖，优于经鼻给予泊沙康唑。
PC1244 有可能成为一种新型的唑类耐药肺部曲霉菌病的局部治疗药物。
