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Outer Membranes of Polymyxin-Resistant Acinetobacter baumannii with Phosphoethanolamine-Modified Lipid A and Lipopolysaccharide Loss Display Different Atomic-Scale Interactions with Polymyxins
journal contribution
posted on 2020-10-09, 00:00 authored by Xukai Jiang, Kai Yang, Mei-Ling Han, Bing Yuan, Jingliang LiJingliang Li, Bin Gong, Tony Velkov, Falk Schreiber, Lushan Wang, Jian LiResistance to the last-line polymyxins is increasingly reported in multidrug-resistant Gram-negative pathogens, including Acinetobacter baumannii, which develops resistance via either lipid A modification (e.g., with phosphoethanolamine [pEtN]) or even lipopolysaccharide (LPS) loss in the outer membrane (OM). Considering these two different mechanisms, quantitative membrane lipidomics data were utilized to develop three OM models representing polymyxin-susceptible and -resistant A. baumannii strains. Through all-atom molecular simulations with enhanced sampling techniques, the effect of lipid A-pEtN modification and LPS loss on the action of colistin (i.e., polymyxin E) was examined for the first time, with a focus on the dynamics and energetics of colistin penetration into these OMs. Lipid A-pEtN modification improved the OM stability, impeding the penetration of colistin into the OM; this differed from the current literature that lipid A-pEtN modification confers resistance by diminishing the initial interaction with polymyxins. In contrast, the LPS deficiency significantly reduced the negative charges on the OM surface, diminishing the binding of colistin. Moreover, both lipid A-pEtN modification and LPS loss also constituted colistin resistance through disturbing the conformational transitions of the colistin molecule. Collectively, atomic-scale interactions between polymyxins and different bacterial OMs are very different and the findings may facilitate the discovery of new-generation polymyxins against Gram-negative ‘superbugs’.
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Journal
ACS Infectious DiseasesVolume
6Issue
10Pagination
2698 - 2708Publisher
American Chemical SocietyLocation
Washington, D.C.Publisher DOI
ISSN
2373-8227eISSN
2373-8227Language
engPublication classification
C Journal article; C1 Refereed article in a scholarly journalUsage metrics
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