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, Jian Li

Research output: Contribution to journalArticleResearchpeer-review

Abstract

Polymyxins are last-line antibiotics against life-threatening multidrug-resistant Gram-negative bacteria. Unfortunately, polymyxin resistance is increasingly reported, leaving a total lack of therapies. Using lipidomics and transcriptomics, we discovered that polymyxin B induced lipid A 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 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-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 thereby confers high-level resistance.

Original languageEnglish
Pages (from-to)121-130
Number of pages10
JournalACS Chemical Biology
Volume13
Issue number1
DOIs
Publication statusPublished - 19 Jan 2018

Cite this

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title = "Polymyxin-Induced Lipid A Deacylation in Pseudomonas aeruginosa Perturbs Polymyxin Penetration and Confers High-Level Resistance",
abstract = "Polymyxins are last-line antibiotics against life-threatening multidrug-resistant Gram-negative bacteria. Unfortunately, polymyxin resistance is increasingly reported, leaving a total lack of therapies. Using lipidomics and transcriptomics, we discovered that polymyxin B induced lipid A 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 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-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 thereby confers high-level resistance.",
author = "Mei-Ling Han and Tony Velkov and Yan Zhu and Roberts, {Kade D.} and {Le Brun}, {Anton P.} and Chow, {Seong Hoong} and Gutu, {Alina D.} and Moskowitz, {Samuel M.} and Hsin-Hui Shen and Jian Li",
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Polymyxin-Induced Lipid A Deacylation in Pseudomonas aeruginosa Perturbs Polymyxin Penetration and Confers High-Level Resistance. / Han, Mei-Ling; Velkov, Tony; Zhu, Yan; Roberts, Kade D.; Le Brun, Anton P.; Chow, Seong Hoong; Gutu, Alina D.; Moskowitz, Samuel M.; Shen, Hsin-Hui; Li, Jian.

In: ACS Chemical Biology, Vol. 13, No. 1, 19.01.2018, p. 121-130.

Research output: Contribution to journalArticleResearchpeer-review

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AU - Han, Mei-Ling

AU - Velkov, Tony

AU - Zhu, Yan

AU - Roberts, Kade D.

AU - Le Brun, Anton P.

AU - Chow, Seong Hoong

AU - Gutu, Alina D.

AU - Moskowitz, Samuel M.

AU - Shen, Hsin-Hui

AU - Li, Jian

PY - 2018/1/19

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N2 - Polymyxins are last-line antibiotics against life-threatening multidrug-resistant Gram-negative bacteria. Unfortunately, polymyxin resistance is increasingly reported, leaving a total lack of therapies. Using lipidomics and transcriptomics, we discovered that polymyxin B induced lipid A 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 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-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 thereby confers high-level resistance.

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