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A nutrient bottleneck controls antibiotic efficacy in structured bacterial populations
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  • Published: 20 February 2026

A nutrient bottleneck controls antibiotic efficacy in structured bacterial populations

  • Anna M. Hancock  ORCID: orcid.org/0000-0003-1717-99781,
  • Arabella S. Dill-Macky  ORCID: orcid.org/0000-0003-4030-84321,
  • Jenna A. Moore  ORCID: orcid.org/0000-0001-6832-06581,
  • Catherine Day2,
  • Mohamed S. Donia  ORCID: orcid.org/0000-0002-9604-29121,2 &
  • …
  • Sujit S. Datta  ORCID: orcid.org/0000-0003-2400-15611,3 

Nature Communications , Article number:  (2026) Cite this article

We are providing an unedited version of this manuscript to give early access to its findings. Before final publication, the manuscript will undergo further editing. Please note there may be errors present which affect the content, and all legal disclaimers apply.

Subjects

  • Biological physics
  • Biomedical engineering
  • Chemical engineering
  • Microbial communities

Abstract

Antibiotic resistance is a growing global health threat. Although antibiotic activity is well studied in homogeneous liquid cultures, many infections are caused by spatially structured multicellular populations where consumption of scarce nutrients establishes strong spatial variations in their abundance. These nutrient variations have long been hypothesized to help bacterial populations tolerate antibiotics, since liquid culture studies link antibiotic tolerance to metabolic activity, and thus, local nutrient availability. Here, we test this hypothesis by visualizing cell death in structured Escherichia coli populations exposed to select nutrients and antibiotics. We find that nutrient availability acts as a bottleneck to antibiotic killing, causing death to propagate through the population as a traveling front. By integrating our measurements with biophysical theory and simulations, we establish quantitative principles that explain how collective nutrient consumption can limit the progression of this “death front,” protecting a population from a nominally deadly antibiotic dose. While increasing nutrient supply can overcome this bottleneck, in some cases, excess nutrient unexpectedly promotes the regrowth of resistant cells. Altogether, this work provides a key step toward predicting and controlling antibiotic treatment of spatially structured bacterial populations, yielding biophysical insights into collective behavior and guiding strategies for effective antibiotic stewardship.

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Data availability

The compressed imaging data generated in this study are provided in the Supplementary Movie files on Zenodo https://zenodo.org/records/14990206. Additional experimental and simulation data generated in this study are provided in the Source Data file. Source data are provided with this paper.

Code availability

The code generated during the current study are available at Code Ocean with DOI: 10.24433/CO.4205040.v1.

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Acknowledgements

We acknowledge support from National Science Foundation (NSF) grants CBET-1941716, DMR-2011750, and EF-2124863 as well as the Camille Dreyfus Teacher-Scholar and Pew Biomedical Scholars Programs, the Eric and Wendy Schmidt Transformative Technology Fund, and the Princeton Catalysis Initiative. This work was supported in part by the NSF Graduate Research Fellowship Program (to A.M.H.) under grant no. DGE-2039656; any opinions, findings, and conclusions or recommendations expressed in this material are those of the authors and do not necessarily reflect the views of the NSF. We thank Katherine Sniezek for constructing the strain used in these experiments and for instructions on the population analysis profiling assay, as well as Mark Brynildsen, Ned Wingreen, Bruce Levin, the late Kevin Wood, and members of the Datta Lab for stimulating discussions and useful feedback.

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Authors and Affiliations

  1. Department of Chemical and Biological Engineering, Princeton University, Princeton, NJ, USA

    Anna M. Hancock, Arabella S. Dill-Macky, Jenna A. Moore, Mohamed S. Donia & Sujit S. Datta

  2. Department of Molecular Biology, Princeton University, Princeton, NJ, USA

    Catherine Day & Mohamed S. Donia

  3. Division of Chemistry and Chemical Engineering, California Institute of Technology, Pasadena, CA, USA

    Sujit S. Datta

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Contributions

A.M.H. and S.S.D. conceptualized and designed the overall research project; A.M.H., A.S.D-M., and C.D. performed all experiments and experimental analyses; A.M.H. developed the theoretical model and performed all calculations and analyses with help from J.A.M.; A.M.H., M.S.D., and S.S.D. wrote the paper.

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Correspondence to Sujit S. Datta.

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Hancock, A.M., Dill-Macky, A.S., Moore, J.A. et al. A nutrient bottleneck controls antibiotic efficacy in structured bacterial populations. Nat Commun (2026). https://doi.org/10.1038/s41467-026-69625-4

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  • Received: 23 June 2025

  • Accepted: 05 February 2026

  • Published: 20 February 2026

  • DOI: https://doi.org/10.1038/s41467-026-69625-4

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