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

JOURNAL OF CONTROLLED RELEASE

卷:259

Article

Zhu, Chongyu¹  Schneider, Elena K.²  Wang, Jiping^2,4  Kempe, Kristian^1,3  Wilson, Paul^1,3  Velkov, Tony²  Li, Jian⁴  Davis, Thomas P.³  Whittaker, Michael R.³  Haddleton, David M.^1,3 

[1] Univ Warwick, Dept Chem, Coventry CV4 7AL, W Midlands, England

[2] Monash Univ, Monash Inst Pharmaceut Sci, Drug Delivery Disposit & Dynam, Parkville, Vic 3052, Australia

[3] Monash Univ, Monash Inst Pharmaceut Sci, ARC Ctr Excellence Convergent Bionano Sci & Techn, Parkville, Vic 3052, Australia

[4] Monash Univ, Monash Biomed Discovery Inst, Dept Microbiol, Clayton, Vic 3800, Australia

关键词: Colistin;    MDR gram-negative bacteria;    Polymeric prodrug;    Traceless linker;    Systemic administration;   

DOI  :  10.1016/j.jconrel.2017.02.005

来源: Elsevier

【 摘 要 】

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 where by 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. (C) 2017 The Authors. Published by Elsevier B.V.

【 授权许可】

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