Polymyxin-induced metabolic perturbations in human lung epithelial cells

Maizbha U. Ahmed, Mohammad A.K. Azad, Mengyao Li, Darren J. Creek, Meiling Han, Fanfan Zhou, Kim Chan, Qi Tony Zhou, Tony Velkov, Jian Li

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1 Citation (Scopus)

Abstract

Inhaled polymyxins are associated with toxicity in human lung epithelial cells that involves multiple apoptotic pathways. However, the mechanism of polymyxin-induced pulmonary toxicity remains unclear. This study aims to investigate polymyxin-induced metabolomic perturbations in human lung epithelial A549 cells. A549 cells were treated with 0.5 or 1.0 mM polymyxin B or colistin for 1, 4, and 24 h. Cellular metabolites were analyzed using liquid chromatography-tandem mass spectrometry (LC-MS/MS), and significantly perturbed metabolites (log2 fold change [log2FC] ≥ 1; false-discovery rate [FDR]≤ 0.2) and key pathways were identified relative to untreated control samples. At 1 and 4 h, very few significant changes in metabolites were observed relative to the untreated control cells. At 24 h, taurine (log2FC = 21.34 6 0.64) and hypotaurine (log2FC = 21.20 ± 0.27) were significantly decreased by 1.0mM polymyxin B. The reduced form of glutathione (GSH) was significantly depleted by 1.0 mM polymyxin B at 24 h (log2FC = 21.80 ± 0.42). Conversely, oxidized glutathione (GSSG) was significantly increased by 1.0 mM both polymyxin B (log2FC = 1.38 ± 0.13 at 4 h and 2.09 ± 0.20 at 24 h) and colistin (log2FC=1.33 ± 0.24 at 24 h). L-Carnitine was significantly decreased by 1.0 mM of both polymyxins at 24 h, as were several key metabolites involved in biosynthesis and degradation of choline and ethanolamine (log2FC ≤ -1); several phosphatidylserines were also increased (log2FC ≥ 1). Polymyxins perturbed key metabolic pathways that maintain cellular redox balance, mitochondrial b-oxidation, and membrane lipid biogenesis. These mechanistic findings may assist in developing new pharmacokinetic/pharmacodynamic strategies to attenuate the pulmonary toxicities of inhaled polymyxins and in the discovery of new-generation polymyxins.

Original languageEnglish
Article number00835
Number of pages13
JournalAntimicrobial Agents and Chemotherapy
Volume65
Issue number9
DOIs
Publication statusPublished - Sep 2021

Keywords

  • Lipid metabolism
  • Lung epithelial cells
  • Metabolomics
  • Mitochondrial toxicity
  • Oxidative stress
  • Polymyxin
  • Respiratory toxicity

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