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Bacterial cell envelope-targeting antibiotics

Nature Reviews Microbiology (2025)Cite this article

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Abstract

The emergence of multidrug-resistant bacteria presents a critical threat to global health. These multidrug-resistant bacteria are often protected by complex cell envelopes that many antibiotics cannot penetrate, creating an important barrier to treatment. In response, targeting bacterial envelopes has long been recognized as an effective strategy, offering potential to bypass the challenges of drug entry and efflux resistance mechanisms. Moreover, many unique bacterial envelope sites remain clinically untapped, and new compounds directed at them have the potential to diversify the space of antimicrobial mechanisms, lowering the risk for cross-resistance. Compounds that target non-proteinaceous envelope components, such as lipopolysaccharide or prenylated peptidoglycan-precursors, are particularly attractive owing to their reduced susceptibility to antimicrobial resistance development. In this Review, we explore both recently discovered compounds and established envelope-targeting antibiotics, including compounds that target Gram-positive bacteria, more complex Gram-negative bacteria and mycobacterial pathogens, shedding light on this still clinically underexplored and vital therapeutic approach.

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Fig. 1: Bacterial cell envelopes.
Fig. 2: The envelope of Gram-positive bacteria as an antibiotic target.
Fig. 3: The envelope of Gram-negative bacteria as an antibiotic target.
Fig. 4: The mycobacterial envelope as an antibiotic target.

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Acknowledgements

Projects in the M.W. laboratory are supported by the European Research Council (ERC) under the European Union’s Horizon 2020 research and innovation programme (grant agreement no. 101045485 to M.W.). A.M.E. is supported by the Biotechnology and Biological Sciences Research Council (BB/Y003667/1) and the National Institute for Health and Care Research Imperial Biomedical Research Centre.

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Authors and Affiliations

  1. NMR Spectroscopy, Bijvoet Centre for Biomolecular Research, Department of Chemistry, Faculty of Science, Utrecht University, Utrecht, The Netherlands

    Charalampos Ntallis & Markus Weingarth

  2. Biological Chemistry Group, Institute of Biology Leiden, Leiden University, Leiden, The Netherlands

    Nathaniel I. Martin

  3. Centre for Bacterial Resistance Biology, Imperial College London, London, UK

    Andrew M. Edwards

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Ntallis, C., Martin, N.I., Edwards, A.M. et al. Bacterial cell envelope-targeting antibiotics. Nat Rev Microbiol (2025). https://doi.org/10.1038/s41579-025-01247-x

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