Peptidic natural products (PNPs) include many antibiotics and other bioactive compounds. While the recent launch of the Global Natural Products Social (GNPS) molecular networking infrastructure is transforming PNP discovery into a high-throughput technology, PNP identification algorithms are needed to realize the potential of the GNPS project. GNPS relies on the assumption that each connected component of a molecular network (representing related metabolites) illuminates the 'dark matter of metabolomics' as long as it contains a known metabolite present in a database. We reveal a surprising diversity of PNPs produced by related bacteria and show that, contrary to the 'comparative metabolomics' assumption, two related bacteria are unlikely to produce identical PNPs (even though they are likely to produce similar PNPs). Since this observation undermines the utility of GNPS, we developed a PNP identification tool, VarQuest, that illuminates the connected components in a molecular network even if they do not contain known PNPs and only contain their variants. VarQuest reveals an order of magnitude more PNP variants than all previous PNP discovery efforts and demonstrates that GNPS already contains spectra from 41% of the currently known PNP families. The enormous diversity of PNPs suggests that biosynthetic gene clusters in various microorganisms constantly evolve to generate a unique spectrum of PNP variants that differ from PNPs in other species.

中文翻译：

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质谱的耐修饰数据库搜索显示出肽类天然产物的多样性增加。

肽类天然产物（PNP）包括许多抗生素和其他生物活性化合物。虽然最近推出的全球天然产物社会（GNPS）分子网络基础设施正在将PNP发现转化为高通量技术，但仍需要PNP识别算法来实现GNPS项目的潜力。GNPS依赖于这样的假设：只要分子网络中每个连接的成分（代表相关代谢物）都包含“代谢组学的暗物质”，只要它包含数据库中存在的已知代谢物即可。我们揭示了相关细菌产生的PNP令人惊讶的多样性，并表明，与“比较代谢组学”假设相反，两个相关细菌不太可能产生相同的PNP（即使它们可能产生相似的PNP）。由于此观察结果破坏了GNPS的实用性，因此我们开发了PNP识别工具VarQuest，该工具可阐明分子网络中连接的组件，即使它们不包含已知的PNP且仅包含其变体。VarQuest揭示了比所有先前的PNP发现工作多一个数量级的PNP变体，并证明GNPS已经包含来自41％的当前已知PNP系列的光谱。PNP的巨大多样性表明，各种微生物中的生物合成基因簇不断演化，以产生不同于其他物种的PNP变体的独特光谱。即使它们不包含已知的PNP，而仅包含其变体，也照亮了分子网络中连接的组件。VarQuest揭示了比所有先前的PNP发现工作多一个数量级的PNP变体，并证明GNPS已经包含来自41％的当前已知PNP系列的光谱。PNP的巨大多样性表明，各种微生物中的生物合成基因簇不断进化，以产生不同于其他物种的PNP变体的独特光谱。即使它们不包含已知的PNP，而仅包含其变体，也照亮了分子网络中连接的组件。VarQuest揭示了比所有先前的PNP发现工作多一个数量级的PNP变体，并证明GNPS已经包含来自41％的当前已知PNP系列的光谱。PNP的巨大多样性表明，各种微生物中的生物合成基因簇不断演化，以产生不同于其他物种的PNP变体的独特光谱。