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

Maytham Hussein, Mei-Ling Han, Yan Zhu, Qi (Tony) Zhou, Yu-Wei Lin, Robert E W Hancock, Daniel Hoyer, Darren J Creek, Jian Li, Tony Velkov

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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.
Original languageEnglish
JournalAntimicrobial Agents and Chemotherapy
DOIs
Publication statusAccepted/In press - 24 Sep 2019

Cite this

@article{86cb03f58b624663bdc54250e63387ad,
title = "Metabolomics study of the synergistic killing of polymyxin B in combination with amikacin against polymyxin-susceptible and resistant Pseudomonas aeruginosa",
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.",
author = "Maytham Hussein and Mei-Ling Han and Yan Zhu and Zhou, {Qi (Tony)} and Yu-Wei Lin and Hancock, {Robert E W} and Daniel Hoyer and Creek, {Darren J} and Jian Li and Tony Velkov",
year = "2019",
month = "9",
day = "24",
doi = "10.1128/AAC.01587-19",
language = "English",
journal = "Antimicrobial Agents and Chemotherapy",
issn = "1098-6596",
publisher = "American Society for Microbiology",

}

Metabolomics study of the synergistic killing of polymyxin B in combination with amikacin against polymyxin-susceptible and resistant Pseudomonas aeruginosa. / Hussein, Maytham; Han, Mei-Ling; Zhu, Yan; Zhou, Qi (Tony); Lin, Yu-Wei; Hancock, Robert E W; Hoyer, Daniel; Creek, Darren J; Li, Jian; Velkov, Tony.

In: Antimicrobial Agents and Chemotherapy, 24.09.2019.

Research output: Contribution to journalArticleResearchpeer-review

TY - JOUR

T1 - Metabolomics study of the synergistic killing of polymyxin B in combination with amikacin against polymyxin-susceptible and resistant Pseudomonas aeruginosa

AU - Hussein, Maytham

AU - Han, Mei-Ling

AU - Zhu, Yan

AU - Zhou, Qi (Tony)

AU - Lin, Yu-Wei

AU - Hancock, Robert E W

AU - Hoyer, Daniel

AU - Creek, Darren J

AU - Li, Jian

AU - Velkov, Tony

PY - 2019/9/24

Y1 - 2019/9/24

N2 - 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.

AB - 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.

U2 - 10.1128/AAC.01587-19

DO - 10.1128/AAC.01587-19

M3 - Article

JO - Antimicrobial Agents and Chemotherapy

JF - Antimicrobial Agents and Chemotherapy

SN - 1098-6596

ER -