Department of Molecular Medicine, Morsani College of Medicine, University of South Florida, 12901 Bruce B. Downs Boulevard, Tampa, FL, 33612, USA.
Department of Infection Control Center of Xiangya Hospital, Central South University, Changsha, 410008, China.
ChemMedChem. 2018 Jul 18;13(14):1414-1420. doi: 10.1002/cmdc.201800240. Epub 2018 Jun 14.
Clostridium difficile infection (CDI) symptoms range from diarrhea to severe toxic megacolon and even death. Due to its rapid acquisition of resistance, C. difficile is listed as an urgent antibiotic-resistant threat, and has surpassed methicillin-resistant Staphylococcus aureus (MRSA) as the most common hospital-acquired infection in the USA. To combat this pathogen, a new structural class of pseudo-peptides that exhibit antimicrobial activities could play an important role. Herein we report a set of bis-cyclic guanidine compounds that show potent antibacterial activity against C. difficile with decent selectivity. Eight compounds showed high in vitro potency against C. difficile UK6 with MIC values of 1.0 μg mL , and cytotoxic selectivity index (SI) values up to 37. Moreover, the most selective compound is also effective in the treatment of C. difficile-induced disease in a mouse model of CDI, and appears to be a very promising new candidate for the treatment of CDI.
艰难梭菌感染（CDI）的症状范围从腹泻到严重的中毒性巨结肠，甚至死亡。由于其迅速获得耐药性，艰难梭菌被列为紧急的抗生素耐药威胁，并且已经超过耐甲氧西林金黄色葡萄球菌（MRSA），成为美国最常见的医院获得性感染。为了对抗这种病原体，一类新的具有抗菌活性的拟肽结构类物质可能会发挥重要作用。在此，我们报告了一组双环胍化合物，它们对艰难梭菌具有很强的抗菌活性，具有良好的选择性。有 8 种化合物对 UK6 表现出很高的体外活性，MIC 值为 1.0μg/mL，细胞毒性选择性指数（SI）值高达 37。此外，最具选择性的化合物在艰难梭菌诱导的 CDI 小鼠模型中也能有效治疗疾病，似乎是一种非常有前途的治疗 CDI 的新候选药物。
