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Cephalosporin resistance, tolerance, and approaches to improve their activities

The Journal of Antibiotics volume 77, pages 135–146 (2024)Cite this article

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Abstract

Cephalosporins comprise a β-lactam antibiotic class whose first members were discovered in 1945 from the fungus Cephalosporium acremonium. Their clinical use for Gram-negative bacterial infections is widespread due to their ability to traverse outer membranes through porins to gain access to the periplasm and disrupt peptidoglycan synthesis. More recent members of the cephalosporin class are administered as last resort treatments for complicated urinary tract infections, MRSA, and other multi-drug resistant pathogens, such as Neisseria gonorrhoeae. Unfortunately, there has been a global increase in cephalosporin-resistant strains, heteroresistance to this drug class has been a topic of increasing concern, and tolerance and persistence are recognized as potential causes of cephalosporin treatment failure. In this review, we summarize the cephalosporin antibiotic class from discovery to their mechanisms of action, and discuss the causes of cephalosporin treatment failure, which include resistance, tolerance, and phenomena when those qualities are exhibited by only small subpopulations of bacterial cultures (heteroresistance and persistence). Further, we discuss how recent efforts with cephalosporin conjugates and combination treatments aim to reinvigorate this antibiotic class.

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Acknowledgements

This work was supported by the 250th Anniversary Fund for Innovation in Undergraduate Education, the Program for Community Engaged Scholarship, and the Council on Science and Technology at Princeton University (MPB). The content is solely the responsibility of the authors and does not necessarily represent the views of the funding agencies.

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  1. These authors contributed equally: Alison H. Araten, Rachel S. Brooks, Sarah D. W. Choi, Laura L. Esguerra, Diana Savchyn, Emily J. Wu

Authors and Affiliations

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

    Alison H. Araten, Sarah D. W. Choi & Mark P. Brynildsen

  2. Department of English, Princeton University, Princeton, NJ, USA

    Rachel S. Brooks

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

    Laura L. Esguerra, Diana Savchyn, Emily J. Wu, Gabrielle Leon, Katherine J. Sniezek & Mark P. Brynildsen

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AHA, RSB, SDWC, LLE, DS, EJW, GL, KJS, and MPB wrote and revised the manuscript.

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Araten, A.H., Brooks, R.S., Choi, S.D.W. et al. Cephalosporin resistance, tolerance, and approaches to improve their activities. J Antibiot 77, 135–146 (2024). https://doi.org/10.1038/s41429-023-00687-y

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