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The polypeptide antibiotic polymyxin B acts as a pro-inflammatory irritant by preferentially targeting macrophages

The Journal of Antibiotics volume 75, pages 29–39 (2022)Cite this article

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Abstract

Polymyxin B (PMB) is an essential antibiotic active against multidrug-resistant bacteria, such as multidrug-resistant Pseudomonas aeruginosa (MDRP). However, the clinical use of PMB is limited, because PMB causes serious side effects, such as nephrotoxicity and neurotoxicity, probably due to its cytotoxic activity. However, cytotoxic mechanisms of PMB are poorly understood. In this study, we found that macrophages are particularly sensitive to PMB, when compared with other types of cells, including fibroblasts and proximal tubule (PT) cells. Of note, PMB-induced necrosis of macrophages allowed passive release of high mobility group box 1 (HMGB1). Moreover, upon exposure of PMB to macrophages, the innate immune system mediated by the NLR family pyrin domain containing 3 (NLRP3) inflammasome that promotes the release of pro-inflammatory cytokines such as interleukin-1β (IL-1β) was stimulated. Interestingly, PMB-induced IL-1β release occurred in the absence of the pore-forming protein gasdermin D (GSDMD), which supports the idea that PMB causes plasma membrane rupture accompanying necrosis. Emerging evidence has suggested that both HMGB1 and IL-1β released from macrophages contribute to excessive inflammation that promote pathogenesis of various diseases, including nephrotoxicity and neurotoxicity. Therefore, these biochemical properties of PMB in macrophages may be associated with the induction of the adverse organ toxicity, which provides novel insights into the mechanisms of PMB-related side effects.

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Acknowledgements

We thank all members of Lab of Health Chemistry for helpful discussions.

Funding

This work was supported by JSPS KAKENHI Grant Numbers JP21H02691 and JP21H02620, MEXT KAKENHI JP21H00268, and by AMED under Grant Number JP19lm0203002. This work was also supported by the Takeda Science Foundation, and the Division for Interdisciplinary Advanced Research and Education (DIARE) Tohoku University.

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  1. These authors contributed equally: Tomohiro Kagi, Rio Naganuma

Authors and Affiliations

  1. Laboratory of Health Chemistry, Graduate School of Pharmaceutical Sciences, Tohoku University, Sendai, Japan

    Tomohiro Kagi, Rio Naganuma, Aya Inoue, Takuya Noguchi, Shuhei Hamano, Yuto Sekiguchi, Yusuke Hirata & Atsushi Matsuzawa

  2. Laboratory of Environmental and Health Sciences, Faculty of Pharmaceutical Sciences, Tohoku Medical and Pharmaceutical University, Sendai, Japan

    Gi-Wook Hwang

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Data curation: T.N., and A.M.; Funding acquisition: T.K., T.N., and A.M.; Investigation: T.K., R.N., A.I., S.H., and Y.S.; Project administration: T.N.; Supervision: A.M.; Writing—original draft: T.N.; Writing—review and editing: A.M.

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Kagi, T., Naganuma, R., Inoue, A. et al. The polypeptide antibiotic polymyxin B acts as a pro-inflammatory irritant by preferentially targeting macrophages. J Antibiot 75, 29–39 (2022). https://doi.org/10.1038/s41429-021-00490-7

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