pt0c00030_si_001.pdf (830.8 kB)
Metabolomic Description of Ivacaftor Elevating Polymyxin B Mediated Antibacterial Activity in Cystic Fibrosis Pseudomonas aeruginosa
journal contribution
posted on 2020-05-07, 19:36 authored by Rafah Allobawi, Drishti P. Ghelani, Elena K. Schneider-FutschikWe have demonstrated that ivacaftor
displays synergistic antibacterial
activity in combination with polymyxin B against polymyxin-resistant Pseudomonas aeruginosa that commonly colonizes the lungs
of people with cystic fibrosis (CF). However, the underlying mechanism(s)
remain unclear. In the present study, we employed untargeted metabolomics
to investigate the synergistic killing mechanism of polymyxin B in
combination with ivacaftor against a polymyxin-susceptible P. aeruginosa FADDI-PA111 (polymyxin B MIC = 2 mg/L) and
a polymyxin-resistant CF P. aeruginosa FADDI-PA006
(polymyxin B MIC = 8 mg/L). Metabolites were extracted at 3 h after
treatments with polymyxin B alone (2 μg/mL for FADDI-PA111 and
4 μg/mL FADDI-PA006 P. aeruginosa), ivacaftor
alone (8 μg/mL), and in combination. Polymyxin B monotherapy
induced significant perturbations in the glycerophospholipid and fatty
acid metabolism pathways against FADDI-PA111 and to a lesser extent
in FADDI-PA006. In both strains, treatment with ivacaftor alone induced
more pronounced perturbations in glycerophospholipid and fatty acid
metabolism pathways than that with polymyxin B alone. This highlights
the unique antimicrobial mode of action of ivacaftor. Pathway analysis
revealed that in combination treatment, polymyxin B mediated killing
is elevated by ivacaftor, largely due to the inhibition of cell envelope
biogenesis via suppression of key membrane lipid metabolites (e.g., sn-glycerol 3-phosphate and sn-glycero-3-phosphoethanolamine)
as well as perturbations in peptidoglycan and lipopolysaccharide biosynthesis.
Furthermore, significant perturbations in the levels of amino sugars
and nucleotide sugars, glycolysis, the tricarboxylic acid cycle, and
pyrimidine ribonucleotide biogenesis were observed with the combination
treatment. These findings provide novel mechanistic information on
the synergistic antibacterial activity of polymyxin–ivacaftor
combination.
History
Usage metrics
Categories
Keywords
combination treatmentacid metabolism pathwayspolymyxin Bpolymyxin-resistant CF Pivacaftorpyrimidine ribonucleotide biogenesiscell envelope biogenesisCystic Fibrosis Pseudomonas aeruginosatricarboxylic acid cycleIvacaftor Elevating Polymyxin B Mediated Antibacterial ActivityFADDI-PA 111aeruginosa FADDI-PA 111polymyxin B MICperturbationpolymyxin-resistant Pseudomonas aeruginosaPolymyxin B monotherapyaeruginosa FADDI-PA 006membrane lipid metabolitesglycerol 3- phosphate
Licence
Exports
RefWorks
BibTeX
Ref. manager
Endnote
DataCite
NLM
DC