Identification and targeting of microbial putrescine acetylation in bloodstream infections
Mayers, J. R.; Varon, J.; Zhou, R. R.; Daniel-Ivad, M.; Beaulieu, C.; Bholse, A.; Glasser, N. R.; Lichtenauer, F. M.; Ng, J.; Pinilla Vera, M.; Huttenhower, C.; Perrella, M. A.; Clish, C. B.; Zhao, S. D.; Baron, R. M.; Balskus, E. P.
Show abstract
The growth of antimicrobial resistance (AMR) has highlighted an urgent need to identify bacterial pathogenic functions that may be targets for clinical intervention. Although severe bacterial infections profoundly alter host metabolism, prior studies have largely ignored alterations in microbial metabolism in this context. Performing metabolomics on patient and mouse plasma samples, we identify elevated levels of bacterially-derived N- acetylputrescine during gram-negative bloodstream infections (BSI), with higher levels associated with worse clinical outcomes. We discover that SpeG is the bacterial enzyme responsible for acetylating putrescine and show that blocking its activity reduces bacterial proliferation and slows pathogenesis. Reduction of SpeG activity enhances bacterial membrane permeability and results in increased intracellular accumulation of antibiotics, allowing us to overcome AMR of clinical isolates both in culture and in vivo. This study highlights how studying pathogen metabolism in the natural context of infection can reveal new therapeutic strategies for addressing challenging infections.
Matching journals
The top 4 journals account for 50% of the predicted probability mass.
Similar papers in this journal
- Decoding a cryptic mechanism of metronidazole resistance among globally disseminated fluoroquinolone-resistant Clostridioides difficile 97%
- Antibiotic hypersensitivity signatures identify targets for attack in the Acinetobacter baumannii cell envelope 97%
- KatG catalase deficiency confers bedaquiline hyper-susceptibility to isoniazid resistant Mycobacterium tuberculosis 96%
Similar papers in this journal
Similar papers in this journal
- The antiphage defense system CBASS controls resistance and enables killing by antifolate antibiotics in Vibrio cholerae 97%
- Cysteine dependence in Lactobacillus iners constitutes a novel therapeutic target to modify the vaginal microbiota 96%
- Glutathione metabolism impacts fungal virulence by modulating the redox environment 96%
Similar papers in this journal
"Similar papers" are the closest papers from that journal in the model's embedding space. They show what the match is built on, but the ranking comes mostly from a classifier over the whole training set, not from these examples alone.