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

Mei-Ling Han, Sue C. Nang, Yu-Wei Lin, Yan Zhu, Heidi H. Yu, Hasini Wickremasinghe, Christopher K. Barlow, Darren J. Creek, Simon Crawford, Gauri Rao, Chongshan Dai, Jeremy J. Barr, Kim Chan, Robert Turner Schooley, Tony Velkov, Jian Li

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Abstract

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 (102 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 log2fold) 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.

Original languageEnglish
Pages (from-to)485-495
Number of pages11
JournalComputational and Structural Biotechnology Journal
Volume20
DOIs
Publication statusPublished - 2022

Keywords

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

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