Comparative metabolomics revealed key pathways associated with the synergistic killing of multidrug-resistant Klebsiella pneumoniae by a bacteriophage-polymyxin combination
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 investi...
| Main Authors: | , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Elsevier
2022-01-01
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| Series: | Computational and Structural Biotechnology Journal |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S2001037022000071 |
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| author | 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 |
| author_facet | 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 |
| author_sort | Mei-Ling Han |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-04-11T05:20:15Z |
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| institution | Directory Open Access Journal |
| issn | 2001-0370 |
| language | English |
| last_indexed | 2024-04-11T05:20:15Z |
| publishDate | 2022-01-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Computational and Structural Biotechnology Journal |
| spelling | doaj.art-2a60c041def3434ca1a2990b057975552022-12-24T04:51:10ZengElsevierComputational and Structural Biotechnology Journal2001-03702022-01-0120485495Comparative metabolomics revealed key pathways associated with the synergistic killing of multidrug-resistant Klebsiella pneumoniae by a bacteriophage-polymyxin combinationMei-Ling Han0Sue C. Nang1Yu-Wei Lin2Yan Zhu3Heidi H. Yu4Hasini Wickremasinghe5Christopher K. Barlow6Darren J. Creek7Simon Crawford8Gauri Rao9Chongshan Dai10Jeremy J. Barr11Kim Chan12Robert Turner Schooley13Tony Velkov14Jian Li15Biomedicine Discovery Institute, Infection and Immunity Program, Department of Microbiology, Monash University, Clayton, Victoria 3800, Australia; Corresponding authors.Biomedicine Discovery Institute, Infection and Immunity Program, Department of Microbiology, Monash University, Clayton, Victoria 3800, AustraliaBiomedicine Discovery Institute, Infection and Immunity Program, Department of Microbiology, Monash University, Clayton, Victoria 3800, AustraliaBiomedicine Discovery Institute, Infection and Immunity Program, Department of Microbiology, Monash University, Clayton, Victoria 3800, AustraliaBiomedicine Discovery Institute, Infection and Immunity Program, Department of Microbiology, Monash University, Clayton, Victoria 3800, AustraliaBiomedicine Discovery Institute, Infection and Immunity Program, Department of Microbiology, Monash University, Clayton, Victoria 3800, AustraliaDepartment of Biochemistry and Molecular Biology, Monash University, Clayton, VIC, Australia; Monash Proteomics and Metabolomics Facility, Monash Biomedicine Discovery Institute, Monash University, Clayton, Victoria 3800, AustraliaMonash Proteomics and Metabolomics Facility, Monash Biomedicine Discovery Institute, Monash University, Clayton, Victoria 3800, Australia; Drug Delivery, Disposition and Dynamics, Monash Institute of Pharmaceutical Sciences, Monash University, 381 Royal Parade, Parkville, Victoria 3052, AustraliaRamaciotti Centre for Cryo Electron Microscopy, Monash University, AustraliaDivision of Pharmacotherapy and Experimental Therapeutics, Eshelman School of Pharmacy, University of North Carolina, Chapel Hill, NC 27599, USADepartment of Veterinary Pharmacology and Toxicology, College of Veterinary Medicine, China Agricultural University, No.2 Yuanmingyuan West Road, Beijing 100193, ChinaSchool of Biological Sciences, Monash University, 25 Rainforest Walk, Clayton, Victoria 3800, AustraliaAdvanced Drug Delivery Group, School of Pharmacy, Faculty of Medicine and Health, The University of Sydney, Sydney, NSW 2006, AustraliaDivision of Infectious Diseases and Global Public Health, Department of Medicine, University of California San Diego, La Jolla, CA, USADepartment of Pharmacology & Therapeutics, School of Biomedical Sciences, Faculty of Medicine, Dentistry and Health Sciences, The University of Melbourne, Parkville, Victoria 3010, AustraliaBiomedicine Discovery Institute, Infection and Immunity Program, Department of Microbiology, Monash University, Clayton, Victoria 3800, Australia; Corresponding authors.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.http://www.sciencedirect.com/science/article/pii/S2001037022000071Klebsiella pneumoniaePolymyxin resistanceBacteriophageMetabolomeCentral carbon metabolism |
| spellingShingle | 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 Comparative metabolomics revealed key pathways associated with the synergistic killing of multidrug-resistant Klebsiella pneumoniae by a bacteriophage-polymyxin combination Computational and Structural Biotechnology Journal Klebsiella pneumoniae Polymyxin resistance Bacteriophage Metabolome Central carbon metabolism |
| title | Comparative metabolomics revealed key pathways associated with the synergistic killing of multidrug-resistant Klebsiella pneumoniae by a bacteriophage-polymyxin combination |
| title_full | Comparative metabolomics revealed key pathways associated with the synergistic killing of multidrug-resistant Klebsiella pneumoniae by a bacteriophage-polymyxin combination |
| title_fullStr | Comparative metabolomics revealed key pathways associated with the synergistic killing of multidrug-resistant Klebsiella pneumoniae by a bacteriophage-polymyxin combination |
| title_full_unstemmed | Comparative metabolomics revealed key pathways associated with the synergistic killing of multidrug-resistant Klebsiella pneumoniae by a bacteriophage-polymyxin combination |
| title_short | Comparative metabolomics revealed key pathways associated with the synergistic killing of multidrug-resistant Klebsiella pneumoniae by a bacteriophage-polymyxin combination |
| title_sort | comparative metabolomics revealed key pathways associated with the synergistic killing of multidrug resistant klebsiella pneumoniae by a bacteriophage polymyxin combination |
| topic | Klebsiella pneumoniae Polymyxin resistance Bacteriophage Metabolome Central carbon metabolism |
| url | http://www.sciencedirect.com/science/article/pii/S2001037022000071 |
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