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The role of bacterial metabolism in antimicrobial resistance

Nature Reviews Microbiology volume 23, pages 439–454 (2025)Cite this article

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Abstract

The relationship between bacterial metabolism and antibiotic treatment is complex. On the one hand, antibiotics leverage cell metabolism to function. On the other hand, increasing research has highlighted that the metabolic state of the cell also impacts all aspects of antibiotic biology, from drug efficacy to the evolution of antimicrobial resistance (AMR). Given that AMR is a growing threat to the current global antibiotic arsenal and ability to treat infectious diseases, understanding these relationships is key to improving both public and human health. However, quantifying the contribution of metabolism to antibiotic activity and subsequent bacterial evolution has often proven challenging. In this Review, we discuss the complex and often bidirectional relationships between metabolism and the various facets of antibiotic treatment and response. We first summarize how antibiotics leverage metabolism for their function. We then focus on the converse of this relationship by specifically delineating the unique contribution of metabolism to three distinct but related arms of antibiotic biology: antibiotic efficacy, AMR evolution and AMR mechanisms. Finally, we note the relevance of metabolism in clinical contexts and explore the future of metabolic-based strategies for personalized antimicrobial therapies. A deeper understanding of these connections is crucial for the broader scientific community to address the growing crisis of AMR and develop future effective therapeutics.

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Fig. 1: Interactions between antibiotics and metabolism.
Fig. 2: Bactericidal and bacteriostatic antibiotics leverage metabolism for their function.
Fig. 3: The unique impact of metabolism on antibiotic resistance, tolerance and lethality in Mycobacterium tuberculosis.
Fig. 4: Unique properties of biofilms confer antibiotic tolerance via altered metabolism.
Fig. 5: Metabolism promotes antimicrobial resistance evolution via its effect on conjugation.
Fig. 6: Classic and metabolic mechanisms of antimicrobial resistance.

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Acknowledgements

This work was supported by the National Institute of Health awards 1R35GM150871-01 (A.J.L.) and R15AI159902-01A1 (R.P.S. and A.J.L.), and the Pew Charitable Trust Foundation (A.J.L.).

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Authors and Affiliations

  1. Weill Cornell Medical College, Cornell University, New York, NY, USA

    Mehrose Ahmad

  2. Department of Chemical Engineering, University of Rochester, Rochester, NY, USA

    Sai Varun Aduru & Allison J. Lopatkin

  3. Cell Therapy Institute, Kiran Patel College of Allopathic Medicine, Nova Southeastern University, Fort Lauderdale, FL, USA

    Robert P. Smith

  4. Department of Medical Education, Kiran Patel College of Allopathic Medicine, Nova Southeastern University, Fort Lauderdale, FL, USA

    Robert P. Smith

  5. Department of Microbiology and Immunology, University of Rochester Medical Center, Rochester, NY, USA

    Zirui Zhao & Allison J. Lopatkin

  6. Department of Biomedical Engineering, University of Rochester Medical Center, Rochester, NY, USA

    Allison J. Lopatkin

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  1. Mehrose Ahmad
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  2. Sai Varun Aduru
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Contributions

M.A., R.P.S., Z.Z. and A.J.L. researched data for the article. M.A., S.V.A. and A.J.L. contributed substantially to discussion of the content. M.A. and A.J.L. wrote the article. M.A., R.P.S., Z.Z. and A.J.L. reviewed and/or edited the manuscript before submission.

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Correspondence to Allison J. Lopatkin.

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Ahmad, M., Aduru, S.V., Smith, R.P. et al. The role of bacterial metabolism in antimicrobial resistance. Nat Rev Microbiol 23, 439–454 (2025). https://doi.org/10.1038/s41579-025-01155-0

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