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Dextrin-Colistin conjugates as a model bioresponsive treatment for multidrug resistant bacterial infections

Ferguson, Elaine L.

, Azzopardi, Ernest

, Roberts, Jessica L., Walsh, Timothy R.

and Thomas, David W.

2014. Dextrin-Colistin conjugates as a model bioresponsive treatment for multidrug resistant bacterial infections. Molecular Pharmaceutics 11 (12) , pp. 4437-4447. 10.1021/mp500584u

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Official URL: http://dx.doi.org/10.1021/mp500584u

Abstract

Polymer therapeutics offer potential benefits in the treatment of multidrug resistant (MDR) infections; affording targeted delivery of biologically active agents to the site of inflammation, potential decreases in systemic toxicity, and the retention of antimicrobial activity at the target site. As a prototype model, these studies developed and characterized a library of dextrin–colistin conjugates (dextrin molecular weight: 7500–48 000 g/mol) as a means of targeting the delivery of colistin. Optimum colistin release kinetics (following dextrin degradation by physiological concentrations of amylase (100 IU/L)) were observed in conjugates containing low molecular weight (∼7500 g/mol) dextrin with ∼1 mol % succinoylation (∼80% drug release within 48 h, compared to ∼33% from sodium colistin methanesulfonate (CMS, Colomycin)). These conjugates exhibited comparable antimicrobial activity to CMS in conventional MIC assays against a range of Gram-negative pathogens, but with significantly reduced in vitro toxicity toward kidney (IC50 = CMS, 15.4 μg/mL; dextrin–colistin, 63.9 μg/mL) and macrophage (IC50 = CMS, 111.3 μg/mL; dextrin–colistin, 303.9 μg/mL) cells. In vivo dose-escalation studies in rats demonstrated improved pharmacokinetics of the conjugates, with prolonged plasma levels of colistin (t1/2 135–1271 min vs 53 min) and decreased toxicity, compared to colistin sulfate. These studies highlight the potential utility of “nanoantibiotic” polymer therapeutics to aid the safe, effective, and targeted delivery of colistin in the management of MDR infections.

Item Type:	Article
Date Type:	Publication
Status:	Published
Schools:	Dentistry Medicine Systems Immunity Research Institute (SIURI)
Subjects:	R Medicine > RK Dentistry R Medicine > RM Therapeutics. Pharmacology
Uncontrolled Keywords:	nanomedicines; PUMPT; polymer therapeutics; infection; bioresponsive; Gram-negative bacteria
Publisher:	American Chemical Society
ISSN:	1543-8384
Date of First Compliant Deposit:	10 June 2019
Date of Acceptance:	31 October 2014
Last Modified:	06 Nov 2024 06:00
URI:	https://orca.cardiff.ac.uk/id/eprint/68623