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首页> 外文期刊>The Journal of Antibiotics: An International Journal >Synergistic combinations of anthelmintic salicylanilides oxyclozanide, rafoxanide, and closantel with colistin eradicates multidrug-resistant colistin-resistant Gram-negative bacilli
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Synergistic combinations of anthelmintic salicylanilides oxyclozanide, rafoxanide, and closantel with colistin eradicates multidrug-resistant colistin-resistant Gram-negative bacilli

机译：Anthelmintic水杨苷氧化物，Rafoxanide和Colistin的闭合蛋白酶的协同组合酸盐酸盐耐热耐药素克阴性杆菌

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摘要

Repurposing nonantibiotic drugs for antimicrobial therapy presents a viable approach to drug discovery. Development of therapeutic strategies that overcome existing resistance mechanisms is important especially against those bacterial infections in which treatment options are limited, such as against multidrug-resistant Gram-negative bacilli. Herein, we provide in vitro data that suggest the addition of anthelmintic salicylanilides, including oxyclozanide, rafoxanide, and closantel, in colistin therapy to treat multidrug-resistant colistin-susceptible but more importantly colistin-resistant Gram-negative bacilli. As a stand-alone agent, the three salicylanilides suffered from limited outer membrane permeation in Pseudomonas aeruginosa, with oxyclozanide also susceptible to efflux. Synergy was apparent for the combinations against multidrug-resistant clinical isolates of P. aeruginosa, Acinetobacter baumannii, Klebsiella pneumoniae, Escherichia coli, and Enterobacter cloacae. Susceptibility breakpoints for colistin, but also with polymyxin B, were reached upon addition of 1 mu g ml(-1) of the corresponding salicylanilide against colistin-resistant Gram-negative bacilli. Furthermore, enhanced bacterial killing was observed in all combinations. Our data corroborate the repositioning of the three salicylanilides as adjuvants to counter resistance to the antibiotic of last resort colistin. Our findings are timely and relevant since the global dissemination of plasmid-mediated colistin resistance had been realized.
机译：重新抑制非抗菌药物的抗菌药物呈现可行的药物发现方法。克服现有抗性机制的治疗策略的发展是重要的，特别是针对那些治疗选择受到限制的细菌感染，例如对多药抗革兰氏阴性芽孢杆菌。在此，我们提供了体外数据，该数据表明在Colistin疗法中添加了含羟基吡啶鎓，包括羟基吡啶鎓，葡萄红烷和闭式蛋白，以治疗多药耐药素易受，但更重要的是耐菌肤耐革兰氏阴性杆菌。作为单独的药剂，在假霉素铜绿假单胞菌中患有有限的外膜渗透的三种水杨酰胺，氧化锆也易于流出。 Synergy对于针对铜绿假单胞菌，鲍氏菌，Klebsiella肺炎群岛，大肠杆菌和肠杆菌肝硬化的多药抗性临床分离株的组合是显而易见的。在加入1μgmml（-1）对应的水杨酰胺上，达到对相应的水杨酰基耐兰蛋白的相应水杨酸盐，达到Colistin的易感性断裂点。此外，在所有组合中观察到增强的细菌杀伤。我们的数据证实了三种水杨酰胺的重新定位作为辅助剂，以对抗最后度假育植物的抗生素的抗性。我们的发现是及时和相关的，因为已经实现了全局传播质粒介导的乳霉素抗性。

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