Overcoming mcr-1 mediated colistin resistance with colistin in combination with other antibiotics.
Overcoming mcr-1 mediated colistin resistance with colistin in combination with other antibiotics.
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DOI：
10.1038/s41467-018-02875-z
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发表时间：
2018-01-31
影响因子：
16.6
通讯作者：
Brown ED
中科院分区：
文献类型：
--
作者：
MacNair CR;Stokes JM;Carfrae LA;Fiebig-Comyn AA;Coombes BK;Mulvey MR;Brown ED
由 mcr-1 介导的质粒传播的粘菌素耐药性可能有助于泛耐药革兰氏阴性菌的传播。在这里，我们证明 mcr-1 赋予对粘菌素诱导的裂解和细菌细胞死亡的抵抗力，但对粘菌素破坏革兰氏阴性外膜的能力提供了最小的保护。事实上，对于表达质粒携带的 mcr-1 的肠杆菌科细菌的粘菌素抗性菌株，临床相关浓度的粘菌素增强了抗生素的作用，而抗生素本身对革兰氏阴性菌没有活性。结果是，几种抗生素与粘菌素联合使用，在低于其相应临床断点的水平下表现出生长抑制作用。此外，粘菌素和克拉霉素联合疗法在临床相关剂量下对小鼠大腿和菌血症感染模型中的 mcr-1 阳性肺炎克雷伯菌显示出疗效。总而言之，这些数据表明，粘菌素与通常对革兰氏阳性菌有效的抗生素联合使用，为表达 mcr-1 的高度耐药性革兰氏阴性病原体提供了一种可行的治疗替代方案。质粒携带的 mcr-1 基因赋予对抗生素粘菌素的抗性。在这里，麦克奈尔等人。然而，表明 mcr-1 阳性细菌容易受到粘菌素介导的外膜破坏的影响，并且可以通过将粘菌素与其他抗生素结合在体外和体内杀死。
Plasmid-borne colistin resistance mediated by mcr-1 may contribute to the dissemination of pan-resistant Gram-negative bacteria. Here, we show that mcr-1 confers resistance to colistin-induced lysis and bacterial cell death, but provides minimal protection from the ability of colistin to disrupt the Gram-negative outer membrane. Indeed, for colistin-resistant strains of Enterobacteriaceae expressing plasmid-borne mcr-1, clinically relevant concentrations of colistin potentiate the action of antibiotics that, by themselves, are not active against Gram-negative bacteria. The result is that several antibiotics, in combination with colistin, display growth-inhibition at levels below their corresponding clinical breakpoints. Furthermore, colistin and clarithromycin combination therapy displays efficacy against mcr-1-positive Klebsiella pneumoniae in murine thigh and bacteremia infection models at clinically relevant doses. Altogether, these data suggest that the use of colistin in combination with antibiotics that are typically active against Gram-positive bacteria poses a viable therapeutic alternative for highly drug-resistant Gram-negative pathogens expressing mcr-1. The plasmid-borne mcr-1 gene confers resistance to the antibiotic colistin. Here, MacNair et al. show that mcr-1 positive bacteria are however susceptible to colistin-mediated disruption of the outer membrane, and can be killed in vitro and in vivo by combining colistin with other antibiotics.
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