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

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 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 Society

Keywords

Lipids, Bacteria, Hydroperoxy radicals, Antibiotics, Immunity, Neutron reflectors, Phospholipids

Citation

Han, 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.7b00836