A traceless reversible polymeric colistin prodrug to combat multidrug-resistant (MDR) gram-negative bacteria.
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 24h. 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.
Department of Chemistry, University of Warwick, CV4 7AL, Coventry, UK.
Chongyu
C
Zhu
Drug Delivery, Disposition and Dynamics, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria 3052, Australia.
Elena K
EK
Schneider
Drug Delivery, Disposition and Dynamics, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria 3052, Australia; Monash Biomedicine Discovery Institute, Department of Microbiology, Monash University, Clayton, Victoria 3800, Australia.
Jiping
J
Wang
ARC Centre of Excellence in Convergent Bio-Nano Science and Technology, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, VIC 3052, Australia; Department of Chemistry, University of Warwick, CV4 7AL, Coventry, UK.
Kristian
K
Kempe
Department of Chemistry, University of Warwick, CV4 7AL, Coventry, UK; ARC Centre of Excellence in Convergent Bio-Nano Science and Technology, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, VIC 3052, Australia.
Paul
P
Wilson
Drug Delivery, Disposition and Dynamics, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria 3052, Australia.
Tony
T
Velkov
Monash Biomedicine Discovery Institute, Department of Microbiology, Monash University, Clayton, Victoria 3800, Australia.
Jian
J
Li
ARC Centre of Excellence in Convergent Bio-Nano Science and Technology, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, VIC 3052, Australia.
Thomas P
TP
Davis
ARC Centre of Excellence in Convergent Bio-Nano Science and Technology, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, VIC 3052, Australia.
Michael R
MR
Whittaker
Department of Chemistry, University of Warwick, CV4 7AL, Coventry, UK; ARC Centre of Excellence in Convergent Bio-Nano Science and Technology, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, VIC 3052, Australia. Electronic address: D.M.Haddleton@warwick.ac.uk.
David M
DM
Haddleton
D019342:Acetic Acid / Q000008:administration & dosage* / Q000737:chemistry / Q000627:therapeutic use; D040981:Acinetobacter baumannii / Q000187:drug effects / Q000254:growth & development; D000818:Animals; D000900:Anti-Bacterial Agents / Q000008:administration & dosage* / Q000737:chemistry / Q000627:therapeutic use; D003091:Colistin / Q000008:administration & dosage* / Q000737:chemistry / Q000627:therapeutic use; D024901:Drug Resistance, Multiple, Bacterial / Q000187:drug effects*; D004952:Esters / Q000008:administration & dosage / Q000737:chemistry / Q000627:therapeutic use; D007668:Kidney / Q000187:drug effects / Q000473:pathology; D051379:Mice; D008826:Microbial Sensitivity Tests; D011092:Polyethylene Glycols / Q000008:administration & dosage* / Q000737:chemistry / Q000627:therapeutic use; D011355:Prodrugs / Q000008:administration & dosage* / Q000737:chemistry / Q000627:therapeutic use; D011552:Pseudomonas Infections / Q000188:drug therapy / Q000382:microbiology / Q000473:pathology; D011550:Pseudomonas aeruginosa / Q000187:drug effects / Q000254:growth & development
D000900:Anti-Bacterial Agents; D004952:Esters; D011355:Prodrugs; D011092:Polyethylene Glycols; D019342:Acetic Acid; D003091:Colistin
Colistin; MDR gram-negative bacteria; Polymeric prodrug; Systemic administration; Traceless linker