The growth of antimicrobial resistance (AMR) highlights an urgent need to identify bacterial pathogenic functions that may be targets for clinical intervention. Although severe infections profoundly alter host metabolism, prior studies have largely ignored microbial metabolism in this context. Here, we describe an iterative, comparative metabolomics pipeline to uncover microbial metabolic features in the complex setting of a host and apply it to investigate gram-negative bloodstream infection (BSI) in patients. We find elevated levels of bacterially derived acetylated polyamines during BSI and discover the enzyme responsible for their production (SpeG). Blocking SpeG activity reduces bacterial proliferation and slows pathogenesis. Reduction of SpeG activity also enhances bacterial membrane permeability and increases intracellular antibiotic accumulation, allowing us to overcome AMR in culture and . This study highlights how tools to study pathogen metabolism in the natural context of infection can reveal and prioritize therapeutic strategies for addressing challenging infections.

中文翻译：

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代谢组学管道强调了血流感染中的微生物代谢


抗菌素耐药性（AMR）的增长凸显了迫切需要确定可能成为临床干预目标的细菌致病功能。尽管严重感染会深刻改变宿主的代谢，但先前的研究在很大程度上忽略了这方面的微生物代谢。在这里，我们描述了一种迭代、比较代谢组学流程，以揭示宿主复杂环境中的微生物代谢特征，并将其应用于研究患者的革兰氏阴性血流感染（BSI）。我们发现 BSI 期间细菌来源的乙酰化多胺水平升高，并发现了负责产生这些乙酰化多胺的酶 (SpeG)。阻断 SpeG 活性可减少细菌增殖并减缓发病机制。 SpeG 活性的降低还可以增强细菌膜的通透性并增加细胞内抗生素的积累，从而使我们能够克服培养物中的 AMR。这项研究强调了在感染的自然背景下研究病原体代谢的工具如何能够揭示和优先考虑解决具有挑战性的感染的治疗策略。