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Causes of polymyxin treatment failure and new derivatives to fill the gap

Abstract

Polymyxins are a class of antibiotics that were discovered in 1947 from programs searching for compounds effective in the treatment of Gram-negative infections. Produced by the Gram-positive bacterium Paenibacillus polymyxa and composed of a cyclic peptide chain with a peptide-fatty acyl tail, polymyxins exert bactericidal effects through membrane disruption. Currently, polymyxin B and colistin (polymyxin E) have been developed for clinical use, where they are reserved as “last-line” therapies for multidrug-resistant (MDR) infections. Unfortunately, the incidences of strains resistant to polymyxins have been increasing globally, and polymyxin heteroresistance has been gaining appreciation as an important clinical challenge. These phenomena, along with bacterial tolerance to this antibiotic class, constitute important contributors to polymyxin treatment failure. Here, we review polymyxins and their mechanism of action, summarize the current understanding of how polymyxin treatment fails, and discuss how the next generation of polymyxins holds promise to invigorate 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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Chiu, S., Hancock, A.M., Schofner, B.W. et al. Causes of polymyxin treatment failure and new derivatives to fill the gap. J Antibiot (2022). https://doi.org/10.1038/s41429-022-00561-3

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