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

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

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish
Pages (from-to)29-39
Number of pages11
JournalJournal of Antibiotics
Volume75
Issue number1
DOIs
Publication statusPublished - 2022 Jan
Externally publishedYes

ASJC Scopus subject areas

  • Pharmacology
  • Drug Discovery

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