4.7 Article

Comparative metabolomics revealed key pathways associated with the synergistic killing of multidrug-resistant Klebsiella pneumoniae by a bacteriophage-polymyxin combination

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ELSEVIER
DOI: 10.1016/j.csbj.2021.12.039

关键词

Klebsiella pneumoniae; Polymyxin resistance; Bacteriophage; Metabolome; Central carbon metabolism

资金

  1. National Institute of Allergy and Infectious Disease (NIAID) of the National Institute of Health [R01 AI132154, R21 AI156766]

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This study demonstrates the efficacy of the combination therapy of polymyxin B and phage against multidrug-resistant Klebsiella pneumoniae, while highlighting the risk of phage monotherapy-induced resistance. The combination treatment significantly inhibits bacterial metabolic activity and activates key cellular signaling pathways within 4 hours.
Resistance to the last-line polymyxins is emerging in multidrug-resistant Klebsiella pneumoniae and phage therapy is a promising alternative. However, phage monotherapy often rapidly causes resistance and few studies have examined antibiotic-phage combinations against K. pneumoniae. Here, we investigated the combination of polymyxin B with a novel phage pK8 against an mcr-1-carrying polymyxin-resistant clinical isolate Kp II-503 (polymyxin B MIC, 8 mg/L). The phage genome was sequenced and bacterial metabolomes were analysed at 4 and 24 h following the treatment with polymyxin B (16 mg/L), phage pK8 (10(2) PFU/mL) and their combination. Minimal metabolic changes across 24 h were observed with polymyxin B alone; whereas a significant inhibition of the citrate cycle, pentose phosphate pathway, amino acid and nucleotide metabolism occurred with the phage-polymyxin combination at both 4 and 24 h, but with phage alone only at 4 h. The development of resistance to phage alone was associated with enhanced membrane lipid and decreased amino acid biosynthesis in Kp II-503. Notably, cAMP, cGMP and cCMP were significantly enriched (3.1-6.6 log(2)fold) by phage alone and the combination only at 4 h. This is the first systems pharmacology study to investigate the enhanced bacterial killing by polymyxin-phage combination and provides important mechanistic information on phage killing, resistance and antibiotic-phage combination in K. pneumoniae. (C) 2022 The Authors. Published by Elsevier B.V. on behalf of Research Network of Computational and Structural Biotechnology.

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