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A new antibiotic selectively kills Gram- negative pathogens

机译：一种新的抗生素选择性杀死革兰氏阴性病原体

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摘要

The current need for novel antibiotics is especially acute for drug-resistant Gram-negative pathogens(1,2). These microorganisms have a highly restrictive permeability barrier, which limits the penetration of most compounds(3,4). As a result, the last class of antibiotics that acted against Gram-negative bacteria was developed in the 1960s(2). We reason that useful compounds can be found in bacteria that share similar requirements for antibiotics with humans, and focus on Photorhabdus symbionts of entomopathogenic nematode microbiomes. Here we report a new antibiotic that we name darobactin, which was obtained using a screen of Photorhabdus isolates. Darobactin is coded by a silent operon with little production under laboratory conditions, and is ribosomally synthesized. Darobactin has an unusual structure with two fused rings that form post-translationally. The compound is active against important Gram-negative pathogens both in vitro and in animal models of infection. Mutants that are resistant to darobactin map to BamA, an essential chaperone and translocator that folds outer membrane proteins. Our study suggests that bacterial symbionts of animals contain antibiotics that are particularly suitable for development into therapeutics.
机译：对于耐药革兰氏阴性病原体，目前对新型抗生素的需求尤为迫切（1,2）。这些微生物具有高度限制的通透性屏障，限制了大多数化合物的渗透（3,4）。结果，在1960年代开发了可抵抗革兰氏阴性细菌的最后一类抗生素（2）。我们认为，可以在与人类对抗生素具有相似要求的细菌中发现有用的化合物，并着重于致病性线虫微生物群的光生菌共生体。在这里，我们报告了一种新的抗生素，我们将其命名为darobactin，它是通过Photorhabdus分离株的筛选获得的。达罗巴汀由沉默的操纵子编码，在实验室条件下几乎不产生，并且是核糖体合成的。达罗布汀具有不寻常的结构，带有两个在翻译后形成的稠合环。该化合物在体外和感染动物模型中均对重要的革兰氏阴性病原体具有活性。对达罗布京具有抗性的突变体会映射到BamA，BamA是折叠外部膜蛋白的必不可少的伴侣和易位分子。我们的研究表明，动物的细菌共生体含有特别适合发展为治疗剂的抗生素。

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