School of Chemistry and Molecular Bioscience, University of Wollongong, Wollongong, NSW, 2522, Australia.
School of Medical and Health Sciences, Edith Cowan University, Western Australia, 6027, Australia.
Eur J Med Chem. 2019 May 15;170:203-224. doi: 10.1016/j.ejmech.2019.02.068. Epub 2019 Mar 1.
Clostridioides (formerly Clostridium) difficile is a Gram-positive anaerobic bacterial pathogen that causes severe gastrointestinal infection in humans. The current chemotherapeutic options are vastly inadequate, expensive and limited; this results in an exorbitant medical and financial burden. New, inexpensive chemotherapeutic treatments for C. difficile infection with improved efficacy are urgently needed. A streamlined synthetic pathway was developed to allow access to 38 novel mono- and di-cationic biaryl 1,2,3-triazolyl peptidomimetics with increased synthetic efficiency, aqueous solubility and enhanced antibacterial efficacy. The monocationic arginine derivative 28 was identified as a potent, Gram-positive selective antibacterial with MIC values of 4 μg/mL against methicillin-resistant Staphylococcus aureus and 8 μg/mL against C. difficile. Furthermore, the dicationic bis-triazole analogue 50 was found to exhibit broad-spectrum activity with substantial Gram-negative efficacy against Acinetobacter baumannii (8 μg/mL), Pseudomonas aeruginosa (8 μg/mL) and Klebsiella pneumoniae (16 μg/mL); additionally, compound 50 displayed reduced haemolytic activity (<13%) in an in vitro haemolysis assay. Membrane-disruption assays were conducted on selected derivatives to confirm the membrane-active mechanism of action inherent to the synthesized amphiphilic compounds. A comparative solubility assay was developed and utilized to optimize the aqueous solubility of the compounds for in vivo studies. The biaryl peptidomimetics 28 and 67 were found to exhibit significant efficacy in an in vivo murine model of C. difficile infection by reducing the severity and slowing the onset of disease.
艰难梭菌（以前称为梭状芽孢杆菌）是一种革兰氏阳性厌氧细菌病原体，可导致人类严重的胃肠道感染。目前的化学治疗选择非常不足，昂贵且有限；这导致了高昂的医疗和经济负担。迫切需要新的、廉价的、治疗艰难梭菌感染的化学治疗方法，以提高疗效。开发了简化的合成途径，以获得 38 种新型单阳离子和双阳离子芳基 1,2,3-三唑基肽模拟物，这些模拟物具有更高的合成效率、水溶性和增强的抗菌功效。单阳离子精氨酸衍生物 28 被鉴定为一种有效的革兰氏阳性选择性抗菌剂，对耐甲氧西林金黄色葡萄球菌的 MIC 值为 4μg/mL，对艰难梭菌的 MIC 值为 8μg/mL。此外，双阳离子双三唑类似物 50 被发现具有广谱活性，对革兰氏阴性菌具有显著的疗效，对鲍曼不动杆菌（8μg/mL）、铜绿假单胞菌（8μg/mL）和肺炎克雷伯菌（16μg/mL）均有疗效；此外，化合物 50 在体外溶血试验中显示出较低的溶血活性（<13%）。对选定的衍生物进行了膜破裂试验，以确认所合成的两亲化合物固有的膜活性作用机制。开发并利用比较溶解度测定法来优化化合物的水溶解度，以进行体内研究。芳基肽模拟物 28 和 67 在艰难梭菌感染的体内小鼠模型中表现出显著的疗效，可降低疾病的严重程度和减缓发病速度。
