Salicylanilide Analog Minimizes Relapse of Clostridioides difficile Infection in Mice
Salicylanilide Analog Minimizes Relapse of Clostridioides difficile Infection in Mice
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DOI：
10.1021/acs.jmedchem.0c00123
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发表时间：
2020-07-09
影响因子：
7.3
通讯作者：
Janda, Kim D.
中科院分区：
文献类型：
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作者：
Blake, Steven;Thanissery, Rajani;Janda, Kim D.
艰难梭菌感染（CDI）会导致严重的，有时是致命的症状，如腹泻和伪膜性结肠炎。尽管存在用于CDI的抗生素，但它们要么昂贵，要么由于它们改变结肠微生物群而导致感染复发，这是抑制感染所必需的。在这里，我们利用了一类已知的膜靶向化合物，我们以前证明这些化合物对多种艰难梭菌菌株具有广泛的抑制活性，同时保留了微生物组以开发有效的药物。合成了一系列新的水杨酰苯胺类化合物，并通过体外抑制试验选择最有效的类似物，以评估其在CDI小鼠模型中的药代动力学参数和效力。结果显示，与标准治疗万古霉素相比，小鼠中CDI的复发率降低，微生物群的干扰减少，从而为可能靶向C细胞膜的新疗法铺平了道路。很难使恢复中的患者的复发最小化。
Clostridioides difficile infection (CDI) causes serious and sometimes fatal symptoms like diarrhea and pseudomem-branous 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 Clostridioides difficile 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 in vitro 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 C. difficile to minimize relapse in the recovering patient.