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 Zhou, Yu Wei Lin, Robert Hancock, Daniel Hoyer, Darren J. Creek, Jian Li, Tony Velkov

Research output: Contribution to journalArticle

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 of Pseudomonas aeruginosa, FADDI-PA111 (MIC + 2 mg/liter for both polymyxin B and amikacin), and a polymyxin-resistant Liverpool epidemic strain (LES), LESB58 (the corresponding MIC for both polymyxin B and amikacin is 16 mg/liter). The metabolites were extracted 15 min, 1 h, and 4 h following treatment with polymyxin B alone (2 mg/liter for FADDI-PA111; 4 mg/liter for LESB58), amikacin alone (2 mg/liter), and both in combination and analyzed using liquid chromatography-mass spectrometry (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 driven initially 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 cell envelope biogenesis and central carbohydrate metabolism, decreased levels of amino sugars, and a downregulated nucleotide pool are the metabolic pathways associated with the synergistic killing of the polymyxin-amikacin combination against P. aeruginosa. This mechanistic study might help optimize synergistic polymyxin B combinations in the clinical setting.

LanguageEnglish
Article numbere01587-19
JournalAntimicrobial Agents and Chemotherapy
Volume64
Issue number1
DOIs
Publication statusPublished - 14 Oct 2019

Keywords

  • Amikacin
  • Metabolomics
  • Polymyxin
  • Pseudomonas aeruginosa

ASJC Scopus subject areas

  • Pharmacology
  • Pharmacology (medical)
  • Infectious Diseases

Cite this

Hussein, Maytham ; Han, Mei Ling ; Zhu, Yan ; Zhou, Qi ; Lin, Yu Wei ; Hancock, Robert ; Hoyer, Daniel ; Creek, Darren J. ; Li, Jian ; Velkov, Tony. / Metabolomics Study of the Synergistic Killing of Polymyxin B in Combination with Amikacin against Polymyxin-Susceptible and -Resistant Pseudomonas aeruginosa. In: Antimicrobial Agents and Chemotherapy. 2019 ; Vol. 64, No. 1.
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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; Lin, Yu Wei; Hancock, Robert; Hoyer, Daniel; Creek, Darren J.; Li, Jian; Velkov, Tony.

In: Antimicrobial Agents and Chemotherapy, Vol. 64, No. 1, e01587-19, 14.10.2019.

Research output: Contribution to journalArticle

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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

AU - Lin, Yu Wei

AU - Hancock, Robert

AU - Hoyer, Daniel

AU - Creek, Darren J.

AU - Li, Jian

AU - Velkov, Tony

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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 of Pseudomonas aeruginosa, FADDI-PA111 (MIC + 2 mg/liter for both polymyxin B and amikacin), and a polymyxin-resistant Liverpool epidemic strain (LES), LESB58 (the corresponding MIC for both polymyxin B and amikacin is 16 mg/liter). The metabolites were extracted 15 min, 1 h, and 4 h following treatment with polymyxin B alone (2 mg/liter for FADDI-PA111; 4 mg/liter for LESB58), amikacin alone (2 mg/liter), and both in combination and analyzed using liquid chromatography-mass spectrometry (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 driven initially 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 cell envelope biogenesis and central carbohydrate metabolism, decreased levels of amino sugars, and a downregulated nucleotide pool are the metabolic pathways associated with the synergistic killing of the polymyxin-amikacin combination against P. aeruginosa. This mechanistic study might help optimize synergistic polymyxin B combinations in the clinical setting.

KW - Amikacin

KW - Metabolomics

KW - Polymyxin

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