Ultrapotent Inhibitor of Clostridioides difficile Growth, Which Suppresses Recurrence In Vivo.
Ultrapotent Inhibitor of Clostridioides difficile Growth, Which Suppresses Recurrence In Vivo.
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DOI：
10.1021/acs.jmedchem.0c01198
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发表时间：
2020-10-22
影响因子：
7.3
通讯作者：
Sintim, Herman O.
中科院分区：
文献类型：
--
作者：
Naclerio, George A.;Abutaleb, Nader S.;Li, Daoyi;Seleem, Mohamed N.;Sintim, Herman O.
艰难梭状芽孢杆菌是美国医疗保健相关感染的主要原因，被疾病控制和预防中心(CDC)视为紧迫威胁。FDA批准只有两种抗生素万古霉素和非达克索米星用于艰难梭菌感染(CDI)的治疗，但这些疗法仍然存在较高的治疗失败率和复发率。因此，需要新的化学实体来治疗CDI。含有N-(1，3，4-恶二唑-2-基)苯甲酰胺的三氟甲硫基对革兰氏阳性菌有很强的抑菌活性(最低抑菌浓度为亚μg/m L)。在这里，我们报告了通过卤素取代显著增强抗菌活性，这提供了新的抗C。具有超强活性的艰难梭菌制剂(MIC低至0.003μg/mL(0.007μM))，超过万古霉素对艰难梭菌临床分离株的活性。该系列中最有希望的化合物HSGN-218对哺乳动物结肠细胞无毒，对肠道有限制作用。此外，HSGN-218还能保护小鼠防止CDI复发。这项工作不仅为艰难梭菌疗法的发展提供了潜在的临床指导，而且它还突出了通过卤素替代显着提高药物效力。
Clostridioides difficile (C. difficile) is the leading cause of healthcare-associated infection in the U.S. and considered an urgent threat by the Centers for Disease Control and Prevention (CDC). Only two antibiotics, vancomycin and fidaxomicin, are FDA-approved for the treatment of C. difficile infection (CDI) but these therapies still suffer from high treatment failure and recurrence. Therefore, new chemical entities to treat CDI are needed. Trifluoromethylthio containing N-(1,3,4-oxadiazol-2-yl)benzamides displayed very potent activities (sub-μg/mL minimum inhibitory concentration (MIC) values) against Gram-positive bacteria. Here, we report remarkable antibacterial activity enhancement via halogen substitutions, which afforded new anti-C. difficile agents with ultrapotent activities (MICs as low as 0.003 μg/mL (0.007 μM)) that surpassed the activity of vancomycin against C. difficile clinical isolates. The most promising compound in the series, HSGN-218, was non-toxic to mammalian colon cells and is gut restrictive. In addition, HSGN-218 protected mice from CDI recurrence. Not only does this work provide a potential clinical lead for the development of C. difficile therapeutics but also it highlights dramatic drug potency enhancement via halogen substitution.
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影响因子：
6.7
作者：
Chumbler NM;Farrow MA;Lapierre LA;Franklin JL;Haslam DB;Goldenring JR;Lacy DB
通讯作者：
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影响因子：
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