摘要
除了传播质粒携带的粘菌素抗性之外，多粘菌素1的使用日益增多，可能会导致我们对抗多重耐药革兰氏阴性病原体的最后一道防线发生严重违反，并预示着真正的泛耐药性感染的出现。粘菌素抗性通常通过用阳离子残基如磷酸乙醇胺共价修饰脂质A而产生，如由Mcr-1介导的（参考文献2） - 其降低多粘菌素对脂多糖的亲和力3。因此，需要新的策略来解决革兰氏阴性菌感染治疗方案数量急剧减少的问题4。消除革兰氏阴性菌的困难很大程度上归因于它们的高度不可渗透的外膜，这对许多其他有效的抗生素起到屏障的作用5。在这里，我们描述了一个非常规的筛选平台，旨在丰富非致死性的外膜活性化合物，并有可能作为传统抗生素的佐剂。该方法通过其与脂多糖的相互作用将抗原虫药pentamidine6鉴定为革兰氏阴性外膜的有效扰动剂。喷他脒显示出与通常局限于革兰氏阳性菌的抗生素的协同作用，产生有效的药物组合，其具有针对广泛的体外革兰氏阴性病原体的活性以及抗小鼠体内鲍曼不动杆菌感染的活性。值得注意的是，喷他脒的佐剂活性在体外和体内持续存在于多粘菌素耐受性细菌中。总体而言，喷他脒及其结构类似物代表用于治疗革兰氏阴性感染的未利用分子，特别是具有获得性多粘菌素耐药决定簇的那些分子。

The increasing use of polymyxins1 in addition to the dissemination of plasmid-borne colistin resistance threatens to cause a serious breach in our last line of defence against multidrug-resistant Gram-negative pathogens, and heralds the emergence of truly pan-resistant infections. Colistin resistance often arises through covalent modification of lipid A with cationic residues such as phosphoethanolamine—as is mediated by Mcr-1 (ref. 2)—which reduce the affinity of polymyxins for lipopolysaccharide3. Thus, new strategies are needed to address the rapidly diminishing number of treatment options for Gram-negative infections4. The difficulty in eradicating Gram-negative bacteria is largely due to their highly impermeable outer membrane, which serves as a barrier to many otherwise effective antibiotics5. Here, we describe an unconventional screening platform designed to enrich for non-lethal, outer-membrane-active compounds with potential as adjuvants for conventional antibiotics. This approach identified the antiprotozoal drug pentamidine6 as an effective perturbant of the Gram-negative outer membrane through its interaction with lipopolysaccharide. Pentamidine displayed synergy with antibiotics typically restricted to Gram-positive bacteria, yielding effective drug combinations with activity against a wide range of Gram-negative pathogens in vitro, and against systemic Acinetobacter baumannii infections in mice. Notably, the adjuvant activity of pentamidine persisted in polymyxin-resistant bacteria in vitro and in vivo. Overall, pentamidine and its structural analogues represent unexploited molecules for the treatment of Gram-negative infections, particularly those having acquired polymyxin resistance determinants.
 
https://www.nature.com/articles/nmicrobiol201728