Departments of Chemistry and Immunology, The Skaggs Institute for Chemical Biology, Worm Institute of Research and Medicine (WIRM), The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, California 92037, United States.
Department of Population Health and Pathobiology, College of Veterinary Medicine, North Carolina State University, Raleigh, North Carolina 27607, United States.
J Med Chem. 2020 Jul 9;63(13):6898-6908. doi: 10.1021/acs.jmedchem.0c00123. Epub 2020 Jun 16.
infection (CDI) causes serious and sometimes fatal symptoms like diarrhea and pseudomembranous colitis. Although antibiotics for CDI exist, they are either expensive or cause recurrence of the infection due to their altering the colonic microbiota, which is necessary to suppress the infection. Here, we leverage a class of known membrane-targeting compounds that we previously showed to have broad inhibitory activity across multiple strains while preserving the microbiome to develop an efficacious agent. A new series of salicylanilides was synthesized, and the most potent analog was selected through an inhibitory assay to evaluate its pharmacokinetic parameters and potency in a CDI mouse model. The results revealed reduced recurrence of CDI and diminished disturbance of the microbiota in mice compared to standard-of-care vancomycin, thus paving the way for novel therapy that can potentially target the cell membrane of to minimize relapse in the recovering patient.
感染（CDI）会导致严重甚至致命的症状，如腹泻和伪膜性结肠炎。尽管有治疗 CDI 的抗生素，但由于它们改变了结肠微生物群，这对于抑制感染是必要的，因此这些抗生素要么昂贵，要么会导致感染复发。在这里，我们利用一类已知的靶向细胞膜的化合物，我们之前曾展示过它们对多种菌株具有广泛的抑制活性，同时保留了微生物组，以开发出一种有效的药物。我们合成了一系列新的水杨酰苯胺，并通过抑制试验选择了最有效的类似物，以评估其在 CDI 小鼠模型中的药代动力学参数和效力。结果表明，与标准护理万古霉素相比，该化合物能降低 CDI 的复发率，并减少对微生物群的干扰，为新的治疗方法铺平了道路，这种治疗方法可能靶向的细胞膜，以最大限度地减少恢复期患者的复发。
