Effect of human urinary microenvironment and fluid flow on antibiotic and phage therapy efficacy against uropathogenic Escherichia coli

Abstract Urinary tract infection (UTI) remains a major global health burden, with frequent recurrences and rising antimicrobial resistance compromising treatment efficacy. Conventional susceptibility assays often fail to predict clinical outcomes, highlighting the need for more physiologically relevant infection models. Here, we investigated how microenvironmental complexity influences uropathogenic Escherichia coli (UPEC) responses to antibiotics and bacteriophages using human urine, a three-dimensional human urothelial microtissue model (3D-UHU), and a novel mesofluidic platform (P-FLO) that applies physiologically relevant wall shear stress to 3D-UHU. Nitrofurantoin showed the greatest potency in conventional susceptibility assays but did not eradicate infection in the static 3D-UHU model. A bacteriophage cocktail (LCPR1) inhibited intracellular bacterial communities, preserved urothelial viability and induced inflammatory cytokine and chemokine secretion. Combined LCPR1 + nitrofurantoin treatment eliminated planktonic bacteria and reduced extracellular and intracellular bacterial communities under static conditions but did not further reduce urothelium-associated bacterial burden compared with nitrofurantoin alone. Under flow, shear stress promoted bacterial elongation, attachment and intracellular community formation, while reducing nitrofurantoin and combination therapy efficacy despite increased drug exposure. These findings demonstrate that the bladder microenvironment profoundly influences UPEC infection dynamics and therapeutic outcomes, underscoring the need for advanced models to guide treatment strategies in the antibiotic resistance era.

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Publication Details

Journal
Nature Communications
Published
2026-09-04
DOI
https://doi.org/10.1038/s41467-026-76589-y
Primary Topic
3D Printing in Biomedical Research
Type
article
Field-Weighted Citation Impact
0.00

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article

Effect of human urinary microenvironment and fluid flow on antibiotic and phage therapy efficacy against uropathogenic Escherichia coli

Aaron Crowther, Dario Carugo, Laia Pasquina-Lemonche, Katie Holden et al.
Nature Communications
3D Printing in Biomedical Research
article

Effect of human urinary microenvironment and fluid flow on antibiotic and phage therapy efficacy against uropathogenic Escherichia coli

Aaron Crowther, Dario Carugo, Laia Pasquina-Lemonche, Katie Holden, Andrew Millard, Davide De Grandi, Ramón Garcia Maset, Nicholas Yuen, Junghee Yoon, Gareth LuTheryn, Gabriele Pollara, Rizka Oktarianti Ainun Jariah, V. H. Chu, Eleanor Stride, Jennifer Rohn, Melissa EK Haines, Benjamin Murray, Francesca Torelli, Dalia Blumgart, Marloes A.E Hodek, Martha R.J. Clokie, James Bancroft, Sara N. H. Alghamd
article en

Abstract

Abstract Urinary tract infection (UTI) remains a major global health burden, with frequent recurrences and rising antimicrobial resistance compromising treatment efficacy. Conventional susceptibility assays often fail to predict clinical outcomes, highlighting the need for more physiologically relevant infection models. Here, we investigated how microenvironmental complexity influences uropathogenic Escherichia coli (UPEC) responses to antibiotics and bacteriophages using human urine, a three-dimensional human urothelial microtissue model (3D-UHU), and a novel mesofluidic platform (P-FLO) that applies physiologically relevant wall shear stress to 3D-UHU. Nitrofurantoin showed the greatest potency in conventional susceptibility assays but did not eradicate infection in the static 3D-UHU model. A bacteriophage cocktail (LCPR1) inhibited intracellular bacterial communities, preserved urothelial viability and induced inflammatory cytokine and chemokine secretion. Combined LCPR1 + nitrofurantoin treatment eliminated planktonic bacteria and reduced extracellular and intracellular bacterial communities under static conditions but did not further reduce urothelium-associated bacterial burden compared with nitrofurantoin alone. Under flow, shear stress promoted bacterial elongation, attachment and intracellular community formation, while reducing nitrofurantoin and combination therapy efficacy despite increased drug exposure. These findings demonstrate that the bladder microenvironment profoundly influences UPEC infection dynamics and therapeutic outcomes, underscoring the need for advanced models to guide treatment strategies in the antibiotic resistance era.

Nature CommunicationsVol. 17(1)
University of Leicester (GB), Universitas Airlangga (ID), Nuffield Orthopaedic Centre (GB), University of Oxford (GB), Kidney Care UK (GB), Science Oxford (GB), Institute of Infection and Immunity (CA), NIHR Leicester Biomedical Research Centre (GB), University College London (GB), University of Sheffield (GB)
National Institute for Health and Care Research, Department of Health and Social Care, University College London Hospitals NHS Foundation Trust, Lembaga Pengelola Dana Pendidikan, Medical Research Council, Engineering and Physical Sciences Research Council, Great Ormond Street Institute of Child Health
Openalex Percentile: Top 99%
3D Printing in Biomedical Research
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