1. A metabolomics pipeline highlights microbial metabolism in bloodstream infections.
- Author
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Mayers JR, Varon J, Zhou RR, Daniel-Ivad M, Beaulieu C, Bhosle A, Glasser NR, Lichtenauer FM, Ng J, Vera MP, Huttenhower C, Perrella MA, Clish CB, Zhao SD, Baron RM, and Balskus EP
- Subjects
- Humans, Animals, Mice, Bacteremia microbiology, Bacteremia metabolism, Bacteremia drug therapy, Anti-Bacterial Agents pharmacology, Gram-Negative Bacterial Infections drug therapy, Gram-Negative Bacterial Infections microbiology, Gram-Negative Bacterial Infections metabolism, Female, Metabolomics, Polyamines metabolism
- Abstract
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 in vivo. 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., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)
- Published
- 2024
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