Lipid A profiling and metabolomics analysis of paired polymyxinsusceptible and-resistant MDR Klebsiella pneumoniae clinical isolates from the same patients before and after colistin treatment

Su Mon Aye, Irene Galani, Mei Ling Han, Ilias Karaiskos, Darren J. Creek, Yan Zhu, Yu Wei Lin, Tony Velkov, Helen Giamarellou, Jian Li

Research output: Contribution to journalArticleResearchpeer-review

Abstract

Background: The increased incidence of polymyxin-resistant MDR Klebsiella pneumoniae has become a major global health concern. Objectives: To characterize the lipid A profiles and metabolome differences between paired polymyxinsusceptible and-resistant MDR K. pneumoniae clinical isolates. Methods: Three pairs of K. pneumoniae clinical isolates from the same patients were examined [ATH 7 (polymyxin B MIC 0.25 mg/L) versus ATH 8 (64 mg/L); ATH 15 (0.5 mg/L) versus ATH 16 (32 mg/L); and ATH 17 (0.5 mg/L) versus ATH 18 (64 mg/L)]. Lipid A and metabolomes were analysed using LC-MS and bioinformatic analysis was conducted. Results: The predominant species of lipid A in all three paired isolates were hexa-Acylated and 4-Amino-4-deoxy-L-Arabinose-modified lipid A species were detected in the three polymyxin-resistant isolates. Significant metabolic differences were evident between the paired isolates. Compared with their corresponding polymyxinsusceptible isolates, the levels of metabolites in amino sugar metabolism (UDP-N-Acetyl-A-D-glucosamine and UDP-N-A-Acetyl-D-mannosaminuronate) and central carbon metabolism (e.g. pentose phosphate pathway and tricarboxylic acid cycle) were significantly reduced in all polymyxin-resistant isolates [fold change (FC) > 1.5, P < 0.05]. Similarly, nucleotides, amino acids and key metabolites in glycerophospholipid metabolism, namely sn-glycerol-3-phosphate and sn-glycero-3-phosphoethanolamine, were significantly reduced across all polymyxin-resistant isolates (FC > 1.5, P < 0.05) compared with polymyxin-susceptible isolates. However, higher glycerophospholipid levels were evident in polymyxin-resistant ATH 8 and ATH 16 (FC > 1.5, P < 0.05) compared with their corresponding susceptible isolates. Conclusions: To our knowledge, this study is the first to reveal significant metabolic perturbations associated with polymyxin resistance in K. pneumoniae.

Original languageEnglish
Pages (from-to)2852-2863
Number of pages12
JournalJournal of Antimicrobial Chemotherapy
Volume75
Issue number10
DOIs
Publication statusPublished - Oct 2020

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