Abstract
Multidrug-resistant Acinetobacter baumannii presents a global medical crisis and polymyxins are used as the last-line therapy. This study aimed to identify metabolic differences between polymyxin-susceptible and polymyxin-resistant A. baumannii using untargeted metabolomics. The metabolome of each A. baumannii strain was measured using liquid chromatography-mass spectrometry. Multivariate and univariate statistics and pathway analyses were employed to elucidate metabolic differences between the polymyxin-susceptible and -resistant A. baumannii strains. Significant differences were identified between the metabolic profiles of the polymyxin-susceptible and -resistant A. baumannii strains. The lipopolysaccharide (LPS) deficient, polymyxin-resistant 19606R showed perturbation in specific amino acid and carbohydrate metabolites, particularly pentose phosphate pathway (PPP) and tricarboxylic acid (TCA) cycle intermediates. Levels of nucleotides were lower in the LPS-deficient 19606R. Furthermore, 19606R exhibited a shift in its glycerophospholipid profile towards increased abundance of short-chain lipids compared to the parent polymyxin-susceptible ATCC 19606. In contrast, in a pair of clinical isolates 03–149.1 (polymyxin-susceptible) and 03–149.2 (polymyxin-resistant, due to modification of lipid A), minor metabolic differences were identified. Notably, peptidoglycan biosynthesis metabolites were significantly depleted in both of the aforementioned polymyxin-resistant strains. This is the first comparative untargeted metabolomics study to show substantial differences in the metabolic profiles of the polymyxin-susceptible and -resistant A. baumannii.
Highlights
With a threat level of “Serious”[5]
Two pairs of A. baumannii strains were examined: a laboratory-derived polymyxin-resistant, LPS-deficient lpxA-mutant strain, 19606R and its polymyxin-susceptible parent strain, ATCC 19606; and two clinical isolates, polymyxin-susceptible 03–149.1 and polymyxin-resistant 03–149.2 obtained from a patient before and after colistin treatment, respectively
Lipid A samples isolated from both polymyxin-susceptible 03–149.1 and polymyxin-resistant 03–149.2 were characterised with electrospray ionization (ESI) high-resolution mass spectrometry in the negative-ion mode (Fig. 1)
Summary
With a threat level of “Serious”[5]. A. baumannii has been characterised as ‘naturally transformable’, since it can rapidly acquire diverse resistance mechanisms and undergo genetic modifications that confer resistance to all current clinically used antibiotics[1,2,6]. Polymyxin resistance in A. baumannii can be acquired via the addition of phosphoethanolamine[14,15] or galactosamine[16] to lipid A structure. Our group firstly reported that A. baumannii ATCC 19606 spontaneously acquired colistin resistance following exposure to high levels of colistin, via the loss of its initial target, LPS17. Transcriptomic analyses of the A. baumannii LPS-deficient strain 19606R revealed significant up-regulation of genes involved in the cell envelope and membrane biogenesis, in particular of the Lol lipoprotein transport system and the Mla-retrograde phospholipid transport system[18]. We report the first comparative untargeted metabolomics analyses of paired polymyxin-susceptible and polymyxin-resistant (via LPS loss or lipid A modifications) A. baumannii strains
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