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Antimicrob Agents Chemother. 2019 Oct 14. pii: AAC.01587-19. doi: 10.1128/AAC.01587-19. [Epub ahead of print]

Metabolomics study of the synergistic killing of polymyxin B in combination with amikacin against polymyxin-susceptible and -resistant Pseudomonas aeruginosa.

Author information

1
Monash Biomedicine Discovery Institute, Department of Microbiology, School of Biomedical Sciences, Faculty of Medicine, Nursing and Health Sciences, Monash University, Melbourne, Australia.
2
Department of Pharmacology & Therapeutics, School of Biomedical Sciences, Faculty of Medicine, Dentistry and Health Sciences, The University of Melbourne, Parkville, VIC, 3010, Australia.
3
Department of Industrial and Physical Pharmacy, College of Pharmacy, Purdue University, West Lafayette, IN 47907, USA.
4
Department of Microbiology and Immunology, Centre for Microbial Diseases and Immunity Research, University of British Columbia, Vancouver, British Columbia, Canada.
5
The Florey Institute of Neuroscience and Mental Health, The University of Melbourne, 30 Royal Parade, Parkville, VIC, 3052, Australia.
6
Department of Molecular Medicine, The Scripps Research Institute, 10550 N. Torrey Pines Road, La Jolla, CA 92037, USA.
7
Drug Delivery, Disposition and Dynamics, Monash Institute of Pharmaceutical Sciences, Monash University, Melbourne 3052, Australia.
8
Monash Biomedicine Discovery Institute, Department of Microbiology, School of Biomedical Sciences, Faculty of Medicine, Nursing and Health Sciences, Monash University, Melbourne, Australia Tony.Velkov@unimelb.edu.au Jian.Li@monash.edu.
9
Department of Pharmacology & Therapeutics, School of Biomedical Sciences, Faculty of Medicine, Dentistry and Health Sciences, The University of Melbourne, Parkville, VIC, 3010, Australia Tony.Velkov@unimelb.edu.au Jian.Li@monash.edu.

Abstract

In the present study, we employed untargeted metabolomics to investigate the synergistic killing mechanism of polymyxin B in combination with an aminoglycoside, amikacin against a polymyxin-susceptible isolate P. aeruginosa FADDI-PA111 (MICs = 2 mg/L for both polymyxin B and amikacin) and a polymyxin-resistant Liverpool Epidemic Strain LESB58 (the corresponding MIC for both polymyxin B and amikacin is 16 mg/L ). The metabolites were extracted at 15 min, 1 and 4 h following treatment with polymyxin B alone (2 mg/L for FADDI-PA111; 4 mg/L for LESB58), amikacin alone (2 mg/L) and in combination; and analyzed using LC-MS. At 15 min and 1 h, polymyxin B alone induced significant perturbations in glycerophospholipid and fatty acid metabolism pathways in FADDI-PA111, and to a lesser extent in LESB58. Amikacin alone at 1 and 4 h induced significant perturbations in peptide and amino acid metabolism, which is in line with the mode of action of aminoglycosides. Pathway analysis of FADDI-PA111 revealed that the synergistic effect of the combination was largely due to the inhibition of cell envelope biogenesis which was initially driven by polymyxin B via suppression of key metabolites involved in lipopolysaccharide, peptidoglycan and membrane lipids (15 min and 1 h) and later by amikacin (4 h). Overall, these novel findings demonstrate that the disruption of the cell envelope biogenesis, central carbohydrate metabolism, decreased levels of amino sugars and a downregulated nucleotide pool are the metabolic pathways associated with the synergistic killing of polymyxin-amikacin combination against P. aeruginosa This mechanistic study might help optimizing synergistic polymyxin B combinations in the clinical setting.

PMID:
31611351
DOI:
10.1128/AAC.01587-19

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