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A traceless reversible polymeric colistin prodrug to combat multidrug-resistant (MDR) gram-negative bacteria

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Zhu, Chongyu, Schneider, Elena K., Wang, Jiping, Kempe, Kristian, Wilson, Paul, Velkov, Tony, Li, Jian, Davis, Thomas P., Whittaker, Michael R. and Haddleton, David M. (2017) A traceless reversible polymeric colistin prodrug to combat multidrug-resistant (MDR) gram-negative bacteria. Journal of Controlled Release, 259 . pp. 83-91. doi:10.1016/j.jconrel.2017.02.005

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Official URL: http://dx.doi.org/10.1016/j.jconrel.2017.02.005

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Abstract

Colistin methanesulfonate (CMS) is the only prodrug of colistin available for clinical use for the treatment of infections caused by multidrug-resistant (MDR) Gram-negative bacteria. Owing to its slow and variable release, an alternative is urgently required to improve effectiveness. Herein we describe a PEGylated colistin prodrug whereby the PEG is attached via a cleavable linker (col-aaPEG) introducing an acetic acid terminated poly (ethylene glycol) methyl ether (aaPEG) onto the Thr residue of colistin. Due to the labile ester containing link, this prodrug is converted back into active colistin in vitro within 24 h. Compared to CMS, it showed a similar or better antimicrobial performance against two MDR isolates of Pseudomonas aeruginosa and Acinetobacter baumannii through in vitro disk diffusion, broth dilution and time-kill studies. In a mouse infection model, col-aaPEG displayed acceptable bacterial killing against P. aeruginosa ATCC 27853 and no nephrotoxicity was found after systemic administration, suggesting it to be a potential alternative for CMS.

Item Type: Journal Article
Subjects: Q Science > QR Microbiology
Divisions: Faculty of Science > Chemistry
Library of Congress Subject Headings (LCSH): Gram-negative bacteria, Multidrug resistance, Bacterial diseases -- Treatment
Journal or Publication Title: Journal of Controlled Release
Publisher: Elsevier
ISSN: 01683659
Official Date: 10 August 2017
Dates:
DateEvent
10 August 2017Published
5 February 2017Available
2 February 2017Accepted
5 December 2016Submitted
Date of first compliant deposit: 22 February 2017
Volume: 259
Page Range: pp. 83-91
DOI: 10.1016/j.jconrel.2017.02.005
Status: Peer Reviewed
Publication Status: Published
Access rights to Published version: Open Access
RIOXX Funder/Project Grant:
Project/Grant IDRIOXX Funder NameFunder ID
1367109[EPSRC] Engineering and Physical Sciences Research Councilhttp://dx.doi.org/10.13039/501100000266
ECF/2015-075 Leverhulme Trusthttp://dx.doi.org/10.13039/501100000275
CE140100036 [ARC] Australian Research Councilhttp://dx.doi.org/10.13039/501100000923
APP1109945National Health and Medical Research Councilhttp://dx.doi.org/10.13039/501100000925
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