摘要

尽管抗生素的广泛应用，传染病仍然是全球死亡的主要原因1。在没有新疗法的情况下，到2050年，由于无法治疗的感染导致的死亡率预计将增加10倍以上。由培养的细菌制成的天然产物（NP）已成为临床上有用的抗生素的主要来源。尽管数十年的生产力，但由于高的再发现率，使用细菌寻找新的抗生素基本上被放弃了。由于在实验室中经常培养出一小部分细菌多样性，并且在发酵实验中仅检测到一小部分由培养细菌编码的化学物质，因此大多数细菌NPs仍然隐藏在全球微生物群中。为了获得这些隐藏的NP，我们开发了一种独立于文化的NP发现平台，该平台涉及从环境样本提取的DNA上捕获的生物合成基因簇的测序，生物信息学分析和异源表达。在这里，我们描述了这个平台的应用，以发现马拉西啶，一种独特的抗生素类，通常编码在土壤微生物群中，但从未在基于文化的NP发现努力中报告。在动物伤口模型中，马来西克酸对多种抗药性病原体具有活性，对甲氧西林抗性金黄色葡萄球菌皮肤感染进行消毒，并且在我们的实验室条件下没有选择抗性。

Despite the wide availability of antibiotics, infectious diseases remain a leading cause of death worldwide1. In the absence of new therapies, mortality rates due to untreatable infections are predicted to rise more than tenfold by 2050. Natural products (NPs) made by cultured bacteria have been a major source of clinically useful antibiotics. In spite of decades of productivity, the use of bacteria in the search for new antibiotics was largely abandoned due to high rediscovery rates. As only a fraction of bacterial diversity is regularly cultivated in the laboratory and just a fraction of the chemistries encoded by cultured bacteria are detected in fermentation experiments, most bacterial NPs remain hidden in the global microbiome. In an effort to access these hidden NPs, we have developed a culture-independent NP discovery platform that involves sequencing, bioinformatic analysis and heterologous expression of biosynthetic gene clusters captured on DNA extracted from environmental samples. Here, we describe the application of this platform to the discovery of the malacidins, a distinctive class of antibiotics that are commonly encoded in soil microbiomes but have never been reported in culture-based NP discovery efforts. The malacidins are active against multidrug-resistant pathogens, sterilize methicillin-resistant Staphylococcus aureus skin infections in an animal wound model and did not select for resistance under our laboratory conditions.

https://www.nature.com/articles/s41564-018-0110-1