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Polymyxin-Induced Lipid A Deacylation in Pseudomonas aeruginosa Perturbs Polymyxin Penetration and Confers High-Level Resistance Mei-Ling Han†‡ , Tony Velkov†§ , Yan Zhu‡ , Kade D. Roberts† , Anton P. Le Brun, Seong Hoong Chow‡ , Alina D. Gutu^ , Samuel M. Moskowitz # , Hsin-Hui Shen*‡ , and Jian Li *‡ † Monash Institute of Pharmaceutical Sciences, Monash University, 381 Royal Parade, Parkville, Victoria 3052, Australia ‡ Monash Biomedicine Discovery Institute, Monash University, Clayton, Victoria 3800, Australia § Department of Pharmacology & Therapeutics, School of Biomedical Sciences, Faculty of Medicine, Dentistry and Health Sciences, The University of Melbourne, Parkville, Victoria 3010, Australia Australian Centre for Neutron Scattering, Australian Nuclear Science and Technology Organisation, Locked Bag 2001, Kirrawee DC, New South Wales 2232, Australia ^ Department of Molecular Biology, Massachusetts General Hospital, Boston, Massachusetts United States # Vertex Pharmaceuticals, Boston, Massachusetts United States Department of Materials Science and Engineering, Faculty of Engineering, Monash University, Clayton, Victoria 3800, Australia
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Cite this: ACS Chem. Biol. 13, 1, 121-130
ACS Chem. Biol., 2018, 13 (1), pp 121–130 DOI: 10.1021/acschembio.7b00836 Publication Date (Web): November 28, 2017 Copyright © 2017 American Chemical Society
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Polymyxins are last-line antibiotics against life-threatening multidrug-resistant Gram-negative
Han, Mei-Ling
bacteria. Unfortunately, polymyxin resistance is increasingly reported, leaving a total lack of
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therapies. Using lipidomics and transcriptomics, we discovered that polymyxin B induced lipid A
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deacylation via pagL in both polymyxin-resistant and -susceptible Pseudomonas aeruginosa. Our results demonstrated that the deacylation of lipid A is an “innate immunity” response to polymyxins and a key compensatory mechanism to the aminoarabinose modification to confer high-level polymyxin resistance in P. aeruginosa. Furthermore, cutting-edge neutron
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reflectometry studies revealed that an assembled outer membrane (OM) with the less hydrophobic penta-acylated lipid A decreased polymyxin B penetration, compared to the hexa-
Received 26 September 2017 Date accepted 28 November 2017 Published online 28 November 2017 Published in print 19 January 2018
acylated form. Polymyxin analogues with enhanced hydrophobicity displayed superior penetration into the tail regions of the penta-acylated lipid A OM. Our findings reveal a previously undiscovered mechanism of polymyxin resistance, wherein polymyxin-induced lipid A remodeling affects the OM packing and hydrophobicity, perturbs polymyxin penetration, and
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thereby confers high-level resistance.
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