Abstract
Background: Polymyxins are a last-line class of antibiotics against multidrug-resistant Acinetobacter baumannii; however, polymyxin resistance can emerge with monotherapy. Therefore, synergistic combination therapy is a crucial strategy to reduce polymyxin resistance.Methods: This study conducted untargeted metabolomics to investigate metabolic responses of a multidrug-resistant (MDR) A. baumannii clinical isolate, AB090342, to colistin and aztreonam alone, and their combination at 1, 4, and 24 h. Metabolomics data were analyzed using univariate and multivariate statistics; metabolites showing ≥ 2-fold changes were subjected to bioinformatics analysis.Results: The synergistic action of colistin-aztreonam combination was initially driven by colistin via significant disruption of bacterial cell envelope, with decreased phospholipid and fatty acid levels at 1 h. Cell wall biosynthesis was inhibited at 4 and 24 h by aztreonam alone and the combination as shown by the decreased levels of two amino sugars, UDP-N-acetylglucosamine and UDP-N-acetylmuramate; these results suggested that aztreonam was primarily responsible for the synergistic killing at later time points. Moreover, aztreonam alone and the combination significantly depleted pentose phosphate pathway, amino acid, peptide and nucleotide metabolism, but elevated fatty acid and key phospholipid levels. Collectively, the combination synergy between colistin and aztreonam was mainly due to the inhibition of cell envelope biosynthesis via different metabolic perturbations.Conclusion: This metabolomics study is the first to elucidate multiple cellular pathways associated with the time-dependent synergistic action of colistin-aztreonam combination against MDR A. baumannii. Our results provide important mechanistic insights into optimizing synergistic colistin combinations in patients.
Highlights
Multidrug-resistant (MDR) Acinetobacter baumannii is an important nosocomial pathogen and can cause ventilatorrelated pneumonia, bloodstream infections, urinary tract infections and meningitis (Dijkshoorn et al, 2007; Fishbain and Peleg, 2010)
The genome sequencing produced 3,246,666 pairs of 300-bp reads for A. baumannii AB090342
Our data showed that AB090342 shared 98.0% sequence similarity to colistin-susceptible A. baumannii AB307-0294 (Genbank Accession No: NC_011595)
Summary
Multidrug-resistant (MDR) Acinetobacter baumannii is an important nosocomial pathogen and can cause ventilatorrelated pneumonia, bloodstream infections, urinary tract infections and meningitis (Dijkshoorn et al, 2007; Fishbain and Peleg, 2010). Polymyxins kill bacterial cells via an initial electrostatic interaction between the positively charged L-α,γ-diaminobutyric acid (Dab) residues of polymyxins and the negatively charged phosphate groups of lipopolysaccharide (LPS) in Gram-negative outer membrane (OM) (Velkov et al, 2010). This is followed by non-polar interactions which allow the hydrophobic moieties (N-terminal fatty acyl tail and D-Phe6-L-Leu7) of polymyxins to penetrate into the OM, disorganize the cell envelope, and result in cell death (Velkov et al, 2010, 2013; Yu et al, 2015; Rabanal and Cajal, 2017). Synergistic combination therapy is a crucial strategy to reduce polymyxin resistance
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