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Hydrolyzable poly[poly(ethylene glycol) methyl ether acrylate]–colistin prodrugs through copper-mediated photoinduced living radical polymerization

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Zhu, Chongyu, Schneider, Elena K., Nikolaou, Vasiliki, Klein, Tobias, Li, Jian, Davis, Thomas P., Whittaker, Michael R., Wilson, Paul, Kempe, Kristian, Velkov, Tony and Haddleton, David M. (2017) Hydrolyzable poly[poly(ethylene glycol) methyl ether acrylate]–colistin prodrugs through copper-mediated photoinduced living radical polymerization. Bioconjugate Chemistry . doi:10.1021/acs.bioconjchem.7b00242 ISSN 1043-1802.

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Official URL: https://doi.org/10.1021/acs.bioconjchem.7b00242

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Abstract

Through the recently developed copper-mediated photoinduced living radical polymerization (CP-LRP), a novel and well-defined polymeric prodrug of the antimicrobial lipopeptide colistin has been developed. A colistin initiator (Boc5-col-Br2) was synthesized through the modification of colistin on both of its threonine residues using a cleavable initiator linker, 2-(2-bromo-2-methylpropanoyloxy) acetic acid (BMPAA), and used for the polymerization of acrylates via CP-LRP. Polymerization proceeds from both sites of the colistin initiator, and through the polymerization of poly(ethylene glycol) methyl ether acrylate (PEGA480), three water-soluble polymer-colistin conjugates (col-PPEGA, having degrees of polymerization of 5, 10, and 20) were achieved with high yield (conversion of ≥93%) and narrow dispersities (Đ < 1.3) in 2-4 h. Little or no effect on the structure and activity of the colistin was observed during the synthesis, and most of the active colistin can be recovered from the conjugates in vitro within 2 days. Furthermore, in vitro biological analyses including disk diffusion, broth microdilution, and time-kill studies suggested that all of the conjugates have the ability to inhibit the growth of multidrug-resistant (MDR) Gram-negative bacteria, of which col-PPEGA DP5 and DP10 showed similar or better antibacterial performance compared to the clinically relevant colistin prodrug CMS, indicating their potential as an alternative antimicrobial therapy. Moreover, considering the control over the polymerization, the CP-LRP technique has the potential to provide an alternative platform for the development of polymer bioconjugates.

Item Type: Journal Article
Subjects: Q Science > QD Chemistry
Q Science > QR Microbiology
R Medicine > RM Therapeutics. Pharmacology
Divisions: Faculty of Science, Engineering and Medicine > Science > Chemistry
SWORD Depositor: Library Publications Router
Library of Congress Subject Headings (LCSH): Prodrugs, Polymerization, Multidrug resistance, Gram-negative bacteria
Journal or Publication Title: Bioconjugate Chemistry
Publisher: American Chemical Society
ISSN: 1043-1802
Official Date: 28 June 2017
Dates:
DateEvent
28 June 2017Published
22 June 2017Accepted
DOI: 10.1021/acs.bioconjchem.7b00242
Status: Peer Reviewed
Publication Status: Published
Reuse Statement (publisher, data, author rights): ** From PubMed via Jisc Publications Router.
Access rights to Published version: Restricted or Subscription Access
Date of first compliant deposit: 11 July 2017
Date of first compliant Open Access: 28 June 2018
RIOXX Funder/Project Grant:
Project/Grant IDRIOXX Funder NameFunder ID
DTA award 1367109[EPSRC] Engineering and Physical Sciences Research Councilhttp://dx.doi.org/10.13039/501100000266
ECF/2015-075Leverhulme Trusthttp://dx.doi.org/10.13039/501100000275
APP1109945National Health and Medical Research Councilhttp://dx.doi.org/10.13039/501100000925
APP1109945[ARC] Australian Research Councilhttp://dx.doi.org/10.13039/501100000923
CE140100036[ARC] Australian Research Councilhttp://dx.doi.org/10.13039/501100000923
R01 AI111965National Institutes of Healthhttp://dx.doi.org/10.13039/100000002
UNSPECIFIEDNational Health and Medical Research Councilhttp://dx.doi.org/10.13039/501100000925
UNSPECIFIEDAustralia. Governmenthttp://viaf.org/viaf/15068752
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