Despite the wide availability of antibiotics, infectious diseases remain a leading cause of death worldwide ¹ . 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^2,3. 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.

中文翻译：

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非培养发现苹果酸作为钙依赖性抗生素，具有对抗多重耐药革兰氏阳性病原体的活性。

尽管抗生素可以广泛使用，但传染病仍然是世界范围内的主要死因¹。在没有新疗法的情况下，到 2050 年，由于无法治愈的感染导致的死亡率预计将上升 10 倍以上。由培养细菌制成的天然产物 (NPs) 一直是临床上有用的抗生素的主要来源。尽管有数十年的生产力，但由于重新发现率高，在寻找新抗生素中使用细菌在很大程度上被放弃了^2,3. 由于只有一小部分细菌多样性在实验室中定期培养，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组中。为了访问这些隐藏的 NP，我们开发了一个独立于培养的 NP 发现平台，该平台涉及从环境样本中提取的 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，我们描述了该平台在发现 malacidins 中的应用，这是一类独特的抗生素，通常编码在土壤微生物组中，但从未在基于培养的 NP 发现工作中报道。malacidins 对多重耐药病原体具有活性，