Department of Pharmaceutical Sciences, Eugene Applebaum College of Pharmacy and Health Sciences , Wayne State University , 259 Mack Avenue , Detroit , Michigan 48201 , United States.
Department of Chemistry and Biochemistry , University of Nevada at Las Vegas , 4505 South Maryland Parkway , Las Vegas , Nevada 89154 , United States.
J Med Chem. 2018 Aug 9;61(15):6759-6778. doi: 10.1021/acs.jmedchem.8b00632. Epub 2018 Jul 30.
Clostridium difficile infections (CDI), particularly those caused by the BI/NAP1/027 epidemic strains, are challenging to treat. One method to address this disease is to prevent the development of CDI by inhibiting the germination of C. difficile spores. Previous studies have identified cholic amide m-sulfonic acid, CamSA, as an inhibitor of spore germination. However, CamSA is inactive against the hypervirulent strain R20291. To circumvent this problem, a series of cholic acid amides were synthesized and tested against R20291. The best compound in the series was the simple phenyl amide analogue which possessed an IC value of 1.8 μM, more than 225 times as potent as the natural germination inhibitor, chenodeoxycholate. This is the most potent inhibitor of C. difficile spore germination described to date. QSAR and molecular modeling analysis demonstrated that increases in hydrophobicity and decreases in partial charge or polar surface area were correlated with increases in potency.
艰难梭菌感染（CDI），特别是由 BI/NAP1/027 流行株引起的感染，治疗具有挑战性。一种解决该疾病的方法是通过抑制艰难梭菌孢子的萌发来预防 CDI 的发生。先前的研究已经确定胆酰胺 m-磺酸（CamSA）是孢子萌发的抑制剂。然而，CamSA 对高毒力株 R20291 没有活性。为了规避这个问题，合成了一系列胆酸酰胺并对 R20291 进行了测试。该系列中最好的化合物是简单的苯甲酰胺类似物，其 IC 值为 1.8 μM，比天然萌发抑制剂鹅脱氧胆酸的效力高 225 倍以上。这是迄今为止描述的最有效的艰难梭菌孢子萌发抑制剂。QSAR 和分子建模分析表明，疏水性的增加和部分电荷或极性表面积的减少与效力的增加相关。
