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Harnessing microbial-derived metabolites in the urinary tract to prevent infection induced catheter encrustation

Author

Listed:
  • L. Beryl Guterman

    (State University of New York at Buffalo)

  • Madalyn Motsay

    (State University of New York at Buffalo)

  • Benjamin C. Hunt

    (State University of New York at Buffalo)

  • Aimee L. Brauer

    (State University of New York at Buffalo)

  • Brian S. Learman

    (State University of New York at Buffalo)

  • Mindula K. Wijayahena

    (The State University of New York)

  • Alexander C. Hoepker

    (The State University of New York
    The State University of New York)

  • Diana S. Aga

    (The State University of New York
    The State University of New York)

  • Brittany Francis

    (State University of New York at Buffalo)

  • Beatriz M. Fontoura

    (Wake Forest University)

  • George L. Donati

    (Wake Forest University
    New York State Department of Health)

  • Peter J. Bush

    (S. Campus)

  • Namrata Deka

    (State University of New York at Buffalo)

  • Chelsie E. Armbruster

    (State University of New York at Buffalo)

Abstract

Proteus mirabilis is a predominant cause of catheter associated urinary tract infection (CAUTI), and a key virulence factor is its urease enzyme which can increase urine pH and form urinary stones, causing catheter blockage and facilitating bacteremia. The only FDA approved urease inhibitor, acetohydroxamic acid (AHA), has side effects that limit its clinical use, necessitating new approaches to target urease activity. We previously discovered that common urinary tract colonizers modulate P. mirabilis urease activity via secreted small molecules. In this study, we conduct a metabolomics analysis of six modulatory bacterial species to reveal urease-dampening metabolites. Of 31 candidate metabolites, seven reproducibly decrease P. mirabilis urease activity. All seven metabolites dampen urease activity in other urease-positive bacterial species, suggesting conserved targets. Six of the metabolites act via mixed inhibition of the urease enzyme. One metabolite, D-imidazole lactate, exhibits a non-competitive mechanism of urease inhibition along with antimicrobial activity and repression of the urease operon in P. mirabilis. Metabolite combinations with AHA demonstrate synergistic activity and prevent catheter encrustation in an in vitro model for CAUTI. Prophylactic use of urease dampening metabolites with AHA could improve the efficacy of antimicrobial treatment against catheter biofilms.

Suggested Citation

  • L. Beryl Guterman & Madalyn Motsay & Benjamin C. Hunt & Aimee L. Brauer & Brian S. Learman & Mindula K. Wijayahena & Alexander C. Hoepker & Diana S. Aga & Brittany Francis & Beatriz M. Fontoura & Geor, 2025. "Harnessing microbial-derived metabolites in the urinary tract to prevent infection induced catheter encrustation," Nature Communications, Nature, vol. 16(1), pages 1-16, December.
    • Handle: RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-64661-y
    DOI: 10.1038/s41467-025-64661-y
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    References listed on IDEAS

    as
    1. Taylor M. Nye & Zongsen Zou & Chloe L. P. Obernuefemann & Jerome S. Pinkner & Erin Lowry & Kent Kleinschmidt & Karla Bergeron & Aleksandra Klim & Karen W. Dodson & Ana L. Flores-Mireles & Jennifer N. , 2024. "Microbial co-occurrences on catheters from long-term catheterized patients," Nature Communications, Nature, vol. 15(1), pages 1-13, December.
    2. Diana Evstafeva & Filip Ilievski & Yinyin Bao & Zhi Luo & Boris Abramovic & Sunghyun Kang & Christian Steuer & Elita Montanari & Tommaso Casalini & Dunja Simicic & Dario Sessa & Stefanita-Octavian Mit, 2024. "Inhibition of urease-mediated ammonia production by 2-octynohydroxamic acid in hepatic encephalopathy," Nature Communications, Nature, vol. 15(1), pages 1-17, December.
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