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Issue 8, 2016
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Polymyxins facilitate entry into mammalian cells

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Abstract

Polymyxin B is an antibiotic used against multi-resistant Gram negative infections, despite observed nephrotoxicity. Here we report the synthesis of functionalized derivatives of polymyxin B and its per-guanidinylated derivative in order to further explore the structural requirements necessary to facilitate uptake of the antibiotic into mammalian cells. We also investigate the possibility of using these novel scaffolds as molecular transporters. At nanomolar concentrations, both are capable of delivering large cargo (>300 kDa) into living cells. Their uptake depends exclusively on cell surface heparan sulfate. Mechanistic studies indicate these novel transporters are internalized through caveolae-mediated pathways and confocal microscopy show colocalization with lysosomes. The polymyxin-based transporters demonstrate cytosolic delivery through the delivery of a ribosome-inactivating protein. Furthermore, the natural polymyxin scaffold can be incorporated into liposomes and enhance their intracellular uptake. In addition to demonstrating the ability of the polymyxin scaffold to facilitate internalization into mammalian cells, these observations suggest the potential use of polymyxin and guanidinopolymyxin for intracellular delivery.

Graphical abstract: Polymyxins facilitate entry into mammalian cells

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Publication details

The article was received on 31 Jan 2016, accepted on 12 Apr 2016 and first published on 25 Apr 2016


Article type: Edge Article
DOI: 10.1039/C6SC00488A
Citation: Chem. Sci., 2016,7, 5059-5068
  • Open access: Creative Commons BY-NC license
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    Polymyxins facilitate entry into mammalian cells

    K. M. Hamill, L. S. McCoy, E. Wexselblatt, J. D. Esko and Y. Tor, Chem. Sci., 2016, 7, 5059
    DOI: 10.1039/C6SC00488A

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