Abstract
Background: Polymyxins are a last-line class of antibiotics against multidrug-resistant Acinetobacter baumannii. However, polymyxin resistance can emerge with monotherapy, highlighting the need for synergistic combination therapies. Polymyxins in combination with β-lactams have shown remarkable synergy against multidrug-resistant A. baumannii. Methods: Liquid chromatography–mass spectrometry-based metabolomics was conducted to investigate the metabolic perturbations in an A. baumannii clinical isolate, AB090342, in response to colistin (1 mg/L), sulbactam (128 mg/L), and their combination at 1, 4, and 24 h. Metabolomics data were analyzed using univariate and multivariate statistics, and metabolites showing ≥2-fold changes were subjected to pathway analysis. Results: The synergistic activity of colistin–sulbactam combination was initially driven by colistin through perturbation of fatty acid and phospholipid levels at 1 h. Cell wall biosynthesis was perturbed by sulbactam alone and the combination over 24 h; this was demonstrated by the decreased levels of two important precursors, uridine diphosphate-N-acetylglucosamine and uridine diphosphate-N-acetylmuramate, together with perturbed lysine and amino sugar metabolism. Moreover, sulbactam alone and the combination significantly depleted nucleotide metabolism and the associated arginine biosynthesis, glutamate metabolism, and pentose phosphate pathway. Notably, the colistin–sulbactam combination decreased amino acid and nucleotide levels more dramatically at 4 h compared with both monotherapies. Conclusions: This is the first metabolomics study revealing the time-dependent synergistic activity of colistin and sulbactam against A. baumannii, which was largely driven by sulbactam through the inhibition of cell wall biosynthesis. Our mechanistic findings may help optimizing synergistic colistin combinations in patients.
Highlights
Multidrug-resistant (MDR) Acinetobacter baumannii is identified as one of the three “critical priority pathogens” by the World Health Organization that urgently require the development of novel therapies (Dijkshoorn et al, 2007; Fishbain and Peleg, 2010)
Cell wall biosynthesis was perturbed by sulbactam alone and the combination over 24 h; this was demonstrated by the decreased levels of two important precursors, uridine diphosphate-N-acetylglucosamine and uridine diphosphate-N-acetylmuramate, together with perturbed lysine and amino sugar metabolism
The colistin–sulbactam combination decreased amino acid and nucleotide levels more dramatically at 4 h compared with both monotherapies
Summary
Multidrug-resistant (MDR) Acinetobacter baumannii is identified as one of the three “critical priority pathogens” by the World Health Organization that urgently require the development of novel therapies (Dijkshoorn et al, 2007; Fishbain and Peleg, 2010). Polymyxins are a family of cyclic lipopeptides with six L-α,γ-diaminobutyric acid (Dab) residues, two hydrophobic amino acids (D-Phe and L-Leu), two L-Thr, and an N-terminal fatty acyl chain (Velkov et al, 2010) Polymyxins exert their antimicrobial activity through an initial polar interaction with the phosphate groups and a subsequent hydrophobic interaction with the fatty acyl chains of the lipid A component of lipopolysaccharide (LPS) in gram-negative bacterial outer membrane (OM) (Velkov et al, 2010; Rabanal and Cajal, 2017). The current understanding of polymyxin resistance in A. baumannii is largely based on covalent modifications of lipid A phosphate groups with positively charged phosphoethanolamine and/or galactosamine moieties as well as the loss of LPS (Moffatt et al, 2010; Arroyo et al, 2011; Boll et al, 2015). Polymyxins in combination with β-lactams have shown remarkable synergy against multidrug-resistant A. baumannii
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