Amixicile, a novel inhibitor of pyruvate: ferredoxin oxidoreductase, shows efficacy against Clostridium difficile in a mouse infection model.
Amixicile, a novel inhibitor of pyruvate: ferredoxin oxidoreductase, shows efficacy against Clostridium difficile in a mouse infection model.
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Amixicile 是一种新型丙酮酸：铁氧还蛋白氧化还原酶抑制剂，在小鼠感染模型中显示出对抗艰难梭菌的功效。
DOI：
10.1128/aac.00360-12
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发表时间：
2012
影响因子：
4.9
通讯作者：
Hoffman,PaulS
中科院分区：
文献类型：
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作者：
Warren,CirleA;vanOpstal,Edward;Ballard,TEric;Kennedy,Andrew;Wang,Xia;Riggins,Mary;Olekhnovich,Igor;Warthan,Michelle;Kolling,GlynisL;Guerrant,RichardL;Macdonald,TimothyL;Hoffman,PaulS
艰难梭菌感染(CDI)是一种严重的腹泻疾病，通常发生在先前使用抗生素后。目前的治疗方法(口服万古霉素和甲硝唑)的主要问题之一是复发率高。Nitazoxanide(NTZ)是厌氧菌、寄生虫、幽门螺杆菌和空肠弯曲杆菌中丙酮酸：铁氧还蛋白氧化还原酶(PFOR)的抑制剂，也显示出对CDI的临床疗效。从ntz的∼250类似物的文库中，我们确定了对PFOR250具有更高效力的先导。MIC筛选表明，对艰难梭菌的体外活性在0.05g/ml至2-μg/ml范围内。为了改善溶解性，我们用丙胺取代了2-乙酰氧基，产生了阿米西林，这是一种可溶性(10 mg/ml)、无毒(基于细胞的分析)的铅，对小鼠口服或腹腔注射(I.P.)没有不良影响。每天200毫克/公斤体重的路线。在接受艰难梭菌致死接种后第1天的初步疗效测试中，阿米西林对小鼠的保护作用在第5天时略低于万古霉素。然而，在优化的CDI模型中，阿米西林在第5天与万古霉素和非达克西星相当，第12天阿米西林的存活率显著高于其他药物。三种药物在体重/体重增加和疾病严重程度方面都是相似的。CDI的复发在接受万古霉素或非达克西星治疗的小鼠中很常见，但在接受阿米昔利或NTZ治疗的小鼠中则不常见。这些结果表明，肠道内有益(非PFOR)细菌的再繁殖，被认为是预防CDI的必要因素，使用阿米西林治疗比使用万古霉素或非达克索米星反弹快得多。如果小鼠模型确实可以预测人类CDI疾病，那么新型PFOR抑制剂阿米昔利似乎是治疗CDI的一个非常有前途的新候选药物。
Clostridium difficile infection (CDI) is a serious diarrheal disease that often develops following prior antibiotic usage. One of the major problems with current therapies (oral vancomycin and metronidazole) is the high rate of recurrence. Nitazoxanide (NTZ), an inhibitor of pyruvate:ferredoxin oxidoreductase (PFOR) in anaerobic bacteria, parasites, Helicobacter pylori, and Campylobacter jejuni, also shows clinical efficacy against CDI. From a library of ∼250 analogues of NTZ, we identified leads with increased potency for PFOR. MIC screens indicatedin vitroactivity in the 0.05- to 2-μg/ml range against C. difficile. To improve solubility, we replaced the 2-acetoxy group with propylamine, producing amixicile, a soluble (10 mg/ml), nontoxic (cell-based assay) lead that produced no adverse effects in mice by oral or intraperitoneal (i.p.) routes at 200 mg/kg of body weight/day. In initial efficacy testing in mice treated (20 mg/kg/day, 5 days each) 1 day after receiving a lethal inoculum of C. difficile, amixicile showed slightly less protection than did vancomycin by day 5. However, in an optimized CDI model, amixicile showed equivalence to vancomycin and fidaxomicin at day 5 and there was significantly greater survival produced by amixicile than by the other drugs on day 12. All three drugs were comparable by measures of weight loss/gain and severity of disease. Recurrence of CDI was common for mice treated with vancomycin or fidaxomicin but not for mice receiving amixicile or NTZ. These results suggest that gut repopulation with beneficial (non-PFOR) bacteria, considered essential for protection against CDI, rebounds much sooner with amixicile therapy than with vancomycin or fidaxomicin. If the mouse model is indeed predictive of human CDI disease, then amixicile, a novel PFOR inhibitor, appears to be a very promising new candidate for treatment of CDI.