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

• DOI: 10.1016/j.csbj.2021.12.039
• Publication Date: 2022-01-06T09:03:41Z
• Authors: Mei-Ling Han; Sue C. Nang; Yu-Wei Lin; Yan Zhu; Heidi H. Yu; Hasini Wickremasi...; Christopher K. Ba...; Darren J. Creek; Simon Crawford; Gauri Rao; Chongshan Dai; Jeremy J. Barr; Kim Chan; Robert Turner Sch...; Tony Velkov; Jian Li
• Keywords: Polymyxin; Polymyxin B; Phage therapy

Resistance to the last-line polymyxins is emerging in multidrug-resistant Klebsiella pneumoniae and phage therapy a promising alternative. However, monotherapy often rapidly causes resistance few studies have examined antibiotic-phage combinations against K. pneumoniae. Here, we investigated combination of polymyxin B with novel pK8 an mcr-1-carrying polymyxin-resistant clinical isolate Kp II-503 (polymyxin MIC, 8 mg/L). The genome was sequenced bacterial metabolomes were analysed at 4 24 h following treatment (16 mg/L), (102 PFU/mL) their combination. Minimal metabolic changes across observed alone; whereas significant inhibition citrate cycle, pentose phosphate pathway, amino acid nucleotide metabolism occurred phage-polymyxin both h, but alone only h. development associated enhanced membrane lipid decreased biosynthesis II-503. Notably, cAMP, cGMP cCMP significantly enriched (3.1-6.6 log2fold) by This first systems pharmacology study investigate killing polymyxin-phage provides important mechanistic information on killing,