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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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WRAP_ch-220217-1-s2.0-s0168365917300585-main1.pdf - Published Version - Requires a PDF viewer. Available under License Creative Commons Attribution 4.0. Download (2549Kb) | Preview |
Official URL: http://dx.doi.org/10.1016/j.jconrel.2017.02.005
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 | |||||||||||||||
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| 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: |
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| 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: |
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