{"doi":"10.1016/j.csbj.2021.12.039","title":"Comparative metabolomics revealed key pathways associated with the synergistic killing of multidrug-resistant <i>Klebsiella pneumoniae</i> by a bacteriophage-polymyxin combination","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.","journal":"Computational and Structural Biotechnology Journal","year":2022,"id":250939,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":25,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9523,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2022-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":842408,"name":"Sue C. Nang","orcid":"0000-0003-0397-820X","position":1,"is_corresponding":false},{"id":366264,"name":"Yu‐Wei Lin","orcid":"0000-0003-2045-6876","position":2,"is_corresponding":false},{"id":326950,"name":"Yan Zhu","orcid":"0000-0001-7342-3782","position":3,"is_corresponding":false},{"id":366260,"name":"Heidi H. Yu","orcid":"0000-0002-3337-1399","position":4,"is_corresponding":false},{"id":366262,"name":"Hasini Wickremasinghe","orcid":"0000-0003-1347-7484","position":5,"is_corresponding":false},{"id":893283,"name":"Christopher K. Barlow","orcid":"0000-0001-9309-2829","position":6,"is_corresponding":false},{"id":304456,"name":"Darren J. Creek","orcid":"0000-0001-7497-7082","position":7,"is_corresponding":false},{"id":893284,"name":"Simon Crawford","orcid":"0000-0002-6740-8743","position":8,"is_corresponding":false},{"id":40493,"name":"Gauri G. Rao","orcid":"0000-0002-8704-7770","position":9,"is_corresponding":false},{"id":282524,"name":"Chongshan Dai","orcid":"0000-0002-4677-0524","position":10,"is_corresponding":false},{"id":321536,"name":"Jeremy J. Barr","orcid":"0000-0001-5603-5294","position":11,"is_corresponding":false},{"id":893698,"name":"Kim H. Chan","orcid":null,"position":12,"is_corresponding":false},{"id":294612,"name":"Robert T. Schooley","orcid":"0000-0002-2498-8426","position":13,"is_corresponding":false},{"id":326951,"name":"Tony Velkov","orcid":"0000-0002-0017-7952","position":14,"is_corresponding":false},{"id":258541,"name":"Jian Li","orcid":"0000-0001-7953-8230","position":15,"is_corresponding":false},{"id":321534,"name":"Mei‐Ling Han","orcid":"0000-0002-0861-2437","position":0,"is_corresponding":true}],"reference_count":57,"raw_metadata":null,"created_at":"2026-07-19T00:24:32.960657Z","pmid":"35070170","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}