1] IBM Almaden Research Center, 650 Harry Road, San Jose, California 95120, USA [2] Department of Polymer Science and Engineering, Yamagata University, Yonezawa, Yamagata 992-8510, Japan [3].
Nat Commun. 2013;4:2861. doi: 10.1038/ncomms3861.
Efficient and pathogen-specific antifungal agents are required to mitigate drug resistance problems. Here we present cationic small molecules that exhibit excellent microbial selectivity with minimal host toxicity. Unlike typical cationic polymers possessing molecular weight distributions, these compounds have an absolute molecular weight aiding in isolation and characterization. However, their specific molecular recognition motif (terephthalamide-bisurea) facilitates spontaneous supramolecular self-assembly manifesting in several polymer-like properties. Computational modelling of the terephthalamide-bisurea structures predicts zig-zag or bent arrangements where distal benzyl urea groups stabilize the high-aspect ratio aqueous supramolecular assemblies. These nanostructures are confirmed by transmission electron microscopy and atomic force microscopy. Antifungal activity against drug-sensitive and drug-resistant strains with in vitro and in vivo biocompatibility is observed. Additionally, despite repeated sub-lethal exposures, drug resistance is not induced. Comparison with clinically used amphotericin B shows similar antifungal behaviour without any significant toxicity in a C. albicans biofilm-induced mouse keratitis model.
需要高效且具有针对性的抗真菌药物来减轻耐药问题。我们在此介绍的阳离子小分子具有出色的微生物选择性，对宿主的毒性极小。与具有分子量分布的典型阳离子聚合物不同，这些化合物具有确定的分子量，有助于分离和表征。然而，其特定的分子识别基序（对苯二甲酰胺-双脲）促进了自发的超分子自组装，表现出多种类似聚合物的特性。对苯二甲酰胺-双脲结构的计算建模预测了锯齿形或弯曲的排列，其中远端苄基脲基团稳定了高纵横比的水相超分子组装体。这些纳米结构通过透射电子显微镜和原子力显微镜得到了证实。观察到这些化合物具有体外和体内生物相容性，对药物敏感和耐药菌株均具有抗真菌活性。此外，尽管反复进行亚致死暴露，也不会诱导产生耐药性。与临床使用的两性霉素 B 相比，在白色念珠菌生物膜诱导的小鼠角膜炎模型中，该化合物表现出相似的抗真菌作用，且没有明显的毒性。
