Xukai Jiang1, Kai Yang2, Bing Yuan2, Meiling Han1, Yan Zhu1, Kade D Roberts1, Nitin A Patil1, Jingliang Li3, Bin Gong4, Robert E W Hancock5, Tony Velkov6, Falk Schreiber7, Lushan Wang8, Jian Li1. 1. Biomedicine Discovery Institute, Infection & Immunity Program and Department of Microbiology, Monash University, Melbourne, Australia. 2. Centre for Soft Condensed Matter Physics and Interdisciplinary Research & School of Physical Science and Technology, Soochow University, Suzhou, China. 3. Institute for Frontier Materials, Deakin University, Geelong, Victoria, Australia. 4. School of Computer Science and Technology, Shandong University, Jinan, China. 5. Department of Microbiology and Immunology, University of British Columbia, Vancouver, Canada. 6. Department of Pharmacology & Therapeutics, University of Melbourne, Melbourne, Australia. 7. Department of Computer and Information Science, University of Konstanz, Konstanz, Germany. 8. State Key Laboratory of Microbial Technology, Shandong University, Qingdao, China.
Abstract
BACKGROUND: MDR bacteria represent an urgent threat to human health globally. Polymyxins are a last-line therapy against life-threatening Gram-negative 'superbugs', including Acinetobacter baumannii. Polymyxins exert antimicrobial activity primarily via permeabilizing the bacterial outer membrane (OM); however, the mechanism of interaction between polymyxins and the OM remains unclear at the atomic level. METHODS: We constructed a lipid A-based OM model of A. baumannii using quantitative membrane lipidomics data and employed all-atom molecular dynamics simulations with umbrella sampling techniques to elucidate the structure-interaction relationship and thermodynamics governing the penetration of polymyxins [B1 and E1 (i.e. colistin A) representing the two clinically used polymyxins] into the OM. RESULTS: Polymyxin B1 and colistin A bound to the A. baumannii OM by the initial electrostatic interactions between the Dab residues of polymyxins and the phosphates of lipid A, competitively displacing the cations from the headgroup region of the OM. Both polymyxin B1 and colistin A formed a unique folded conformation upon approaching the hydrophobic centre of the OM, consistent with previous experimental observations. Polymyxin penetration induced reorientation of the headgroups of the OM lipids near the penetration site and caused local membrane disorganization, thereby significantly increasing membrane permeability and promoting the subsequent penetration of polymyxin molecules into the OM and periplasmic space. CONCLUSIONS: The thermodynamics governing the penetration of polymyxins through the outer leaflet of the A. baumannii OM were examined and novel structure-interaction relationship information was obtained at the atomic and membrane level. Our findings will facilitate the discovery of novel polymyxins against MDR Gram-negative pathogens.
BACKGROUND: MDR bacteria represent an urgent threat to human health globally. Polymyxins are a last-line therapy against life-threatening Gram-negative 'superbugs', including Acinetobacter baumannii. Polymyxins exert antimicrobial activity primarily via permeabilizing the bacterial outer membrane (OM); however, the mechanism of interaction between polymyxins and the OM remains unclear at the atomic level. METHODS: We constructed a lipid A-based OM model of A. baumannii using quantitative membrane lipidomics data and employed all-atom molecular dynamics simulations with umbrella sampling techniques to elucidate the structure-interaction relationship and thermodynamics governing the penetration of polymyxins [B1 and E1 (i.e. colistin A) representing the two clinically used polymyxins] into the OM. RESULTS: Polymyxin B1 and colistin A bound to the A. baumannii OM by the initial electrostatic interactions between the Dab residues of polymyxins and the phosphates of lipid A, competitively displacing the cations from the headgroup region of the OM. Both polymyxin B1 and colistin A formed a unique folded conformation upon approaching the hydrophobic centre of the OM, consistent with previous experimental observations. Polymyxin penetration induced reorientation of the headgroups of the OM lipids near the penetration site and caused local membrane disorganization, thereby significantly increasing membrane permeability and promoting the subsequent penetration of polymyxin molecules into the OM and periplasmic space. CONCLUSIONS: The thermodynamics governing the penetration of polymyxins through the outer leaflet of the A. baumannii OM were examined and novel structure-interaction relationship information was obtained at the atomic and membrane level. Our findings will facilitate the discovery of novel polymyxins against MDR Gram-negative pathogens.
Authors: Roger L Nation; Jian Li; Otto Cars; William Couet; Michael N Dudley; Keith S Kaye; Johan W Mouton; David L Paterson; Vincent H Tam; Ursula Theuretzbacher; Brian T Tsuji; John D Turnidge Journal: Lancet Infect Dis Date: 2014-10-21 Impact factor: 25.071
Authors: Tony Velkov; Kade D Roberts; Roger L Nation; Jiping Wang; Philip E Thompson; Jian Li Journal: ACS Chem Biol Date: 2014-03-17 Impact factor: 5.100
Authors: Xukai Jiang; Kai Yang; Bing Yuan; Bin Gong; Lin Wan; Nitin A Patil; James D Swarbrick; Kade D Roberts; Falk Schreiber; Lushan Wang; Tony Velkov; Jian Li Journal: J Biol Chem Date: 2020-09-10 Impact factor: 5.157