title: Global metabolic analyses identify key differences in metabolite levels between polymyxin-susceptible and polymyxin-resistant Acinetobacter baumannii.
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.
authors.affiliation: Drug Delivery, Disposition and Dynamics, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, VIC, 3052, Australia.
authors.forename: Mohd Hafidz Mahamad
authors.initials: MH
authors.lastname: Maifiah
authors.affiliation: Drug Delivery, Disposition and Dynamics, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, VIC, 3052, Australia.
authors.forename: Soon-Ee
authors.initials: SE
authors.lastname: Cheah
authors.affiliation: Drug Delivery, Disposition and Dynamics, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, VIC, 3052, Australia.
authors.forename: Matthew D
authors.initials: MD
authors.lastname: Johnson
authors.affiliation: Drug Delivery, Disposition and Dynamics, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, VIC, 3052, Australia.
authors.forename: Mei-Ling
authors.initials: ML
authors.lastname: Han
authors.affiliation: Department of Microbiology, Faculty of Medicine, Nursing &Health Sciences, Monash University, Clayton, VIC, 3800, Australia.
authors.forename: John D
authors.initials: JD
authors.lastname: Boyce
authors.affiliation: Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, 10700, Thailand.
authors.forename: Visanu
authors.initials: V
authors.lastname: Thamlikitkul
authors.affiliation: UNC Eshelman School of Pharmacy, The University of North Carolina at Chapel Hill, Chapel Hill, NC, 27599-7569, USA.
authors.forename: Alan
authors.initials: A
authors.lastname: Forrest
authors.affiliation: Detroit Medical Centre and Wayne State University, University Health Centre, Detroit, MI, 48201, USA.
authors.forename: Keith S
authors.initials: KS
authors.lastname: Kaye
authors.affiliation: Hudson Institute of Medical Research, Clayton, VIC, 3168, Australia.|Faculty of Medicine, Nursing &Health Sciences, Monash University, Clayton, VIC, 3800, Australia.
authors.forename: Paul
authors.initials: P
authors.lastname: Hertzog
authors.affiliation: Department of Biochemistry and Molecular Biology, Faculty of Medicine, Nursing &Health Sciences, Monash University, Clayton, VIC, 3800, Australia.
authors.forename: Anthony W
authors.initials: AW
authors.lastname: Purcell
authors.affiliation: Department of Biochemistry and Molecular Biology, Faculty of Medicine, Nursing &Health Sciences, Monash University, Clayton, VIC, 3800, Australia.
authors.forename: Jiangning
authors.initials: J
authors.lastname: Song
authors.affiliation: Drug Delivery, Disposition and Dynamics, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, VIC, 3052, Australia.
authors.forename: Tony
authors.initials: T
authors.lastname: Velkov
authors.affiliation: Drug Delivery, Disposition and Dynamics, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, VIC, 3052, Australia.
authors.forename: Darren J
authors.initials: DJ
authors.lastname: Creek
authors.affiliation: Drug Delivery, Disposition and Dynamics, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, VIC, 3052, Australia.
authors.forename: Jian
authors.initials: J
authors.lastname: Li
mesh_terms: D040981:Acinetobacter baumannii / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism*; D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D016000:Cluster Analysis; D024881:Drug Resistance, Bacterial; D024901:Drug Resistance, Multiple, Bacterial; D004734:Energy Metabolism / Q000187:drug effects; D023281:Genomics / Q000379:methods; D008050:Lipid A / Q000737:chemistry / Q000378:metabolism; D013058:Mass Spectrometry; D055442:Metabolome; D055432:Metabolomics / Q000379:methods; D008826:Microbial Sensitivity Tests; D011113:Polymyxins / Q000494:pharmacology*
chemical_list: D000900:Anti-Bacterial Agents; D008050:Lipid A; D011113:Polymyxins