Polymyxin-induced lipid A deacylation in pseudomonas aeruginosa perturbs polymyxin penetration and confers high-level resistance

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dc.contributor.authorHan, MLen_AU
dc.contributor.authorVelkov, Ten_AU
dc.contributor.authorZhu, Yen_AU
dc.contributor.authorRoberts, KDen_AU
dc.contributor.authorLe Brun, APen_AU
dc.contributor.authorChow, SHen_AU
dc.contributor.authorGutu, ADen_AU
dc.contributor.authorMoskowitz, SMen_AU
dc.contributor.authorShen, HHen_AU
dc.contributor.authorLi, Jen_AU
dc.date.accessioned2021-01-11T01:20:03Zen_AU
dc.date.available2021-01-11T01:20:03Zen_AU
dc.date.issued2017-11-28en_AU
dc.date.statistics2021-01-08en_AU
dc.description.abstractPolymyxins 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 viapagL 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. © 2017 American Chemical Societyen_AU
dc.identifier.citationHan, M.-L., Velkov, T., Zhu, Y., Roberts, K. D., Le Brun, A. P., Chow, S. H., Gutu, A. D., Moskowitz, S. M. Shen, H.-J. & Li, J. (2018). Polymyxin-induced lipid A deacylation in pseudomonas aeruginosa perturbs polymyxin penetration and confers high-level resistance. ACS Chemical Biology, 13(1), 121-130. doi:10.1021/acschembio.7b00836en_AU
dc.identifier.issn1554-8929en_AU
dc.identifier.issue1en_AU
dc.identifier.journaltitleACS Chemical Biologyen_AU
dc.identifier.pagination121-130en_AU
dc.identifier.urihttps://doi.org/10.1021/acschembio.7b00836en_AU
dc.identifier.urihttps://apo.ansto.gov.au/dspace/handle/10238/10230en_AU
dc.identifier.volume13en_AU
dc.language.isoenen_AU
dc.publisherACS Publicationsen_AU
dc.subjectLipidsen_AU
dc.subjectBacteriaen_AU
dc.subjectHydroperoxy radicalsen_AU
dc.subjectAntibioticsen_AU
dc.subjectImmunityen_AU
dc.subjectNeutron reflectorsen_AU
dc.subjectPhospholipidsen_AU
dc.titlePolymyxin-induced lipid A deacylation in pseudomonas aeruginosa perturbs polymyxin penetration and confers high-level resistanceen_AU
dc.typeJournal Articleen_AU
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