C109 is a potent but poorly soluble FtsZ inhibitor displaying promising activity against Burkholderia cenocepacia, a high-risk pathogen for cystic fibrosis (CF) sufferers. To harness C109 for inhalation, we developed nanocrystal-embedded dry powders for inhalation suspension consisting in C109 nanocrystals stabilized with D-α-tocopheryl polyethylene glycol 1000 succinate (TPGS) embedded in hydroxypropyl-β-cyclodextrin (CD). The powders could be safely re-dispersed in water for in vitro aerosolization. Owing to the presence of a PEG shell, the rod shape and the peculiar aspect ratio, C109 nanocrystals were able to diffuse through artificial CF mucus. The promising technological features were completed by encouraging in vitro/in vivo effects. The formulations displayed no toxicity towards human bronchial epithelial cells and were active against planktonic and sessile B. cenocepacia strains. The efficacy of C109 nanosuspensions in combination with piperacillin was confirmed in a Galleria mellonella infection model, strengthening their potential for combined therapy of B. cenocepacia lung infections.

C109是一种有效的但难溶的FtsZ抑制剂，对Burkholderia cenocepacia（对囊性纤维化（CF）病人而言是高风险的病原体）表现出有希望的活性。为了利用C109进行吸入，我们开发了用于吸入悬浮液的纳米晶体嵌入式干粉，该干粉由C109纳米晶体组成，该C109纳米晶体用嵌入羟丙基-β-环糊精（CD）中的D-α-生育酚聚乙二醇1000琥珀酸酯（TPGS）稳定。可以将这些粉末安全地重新分散在水中以进行体外雾化。由于存在PEG壳，棒状形状和特殊的长宽比，C109纳米晶体能够通过人造CF粘液扩散。令人鼓舞的技术特征是通过鼓励实现的体外/体内效应。该制剂对人支气管上皮细胞没有毒性，并且对浮游和无柄的B. cenocepacia菌株具有活性。在梅勒埃里亚菌感染模型中证实了C109纳米混悬液与哌拉西林联用的功效，从而增强了它们联合治疗新陈皮芽孢杆菌肺部感染的潜力。