A novel class of bioresponsive nanomedicines for localised reinstatement of bioactivity and specific targeting

Abstract

Gram-negative infection is a global health concern. We present a custom-engineered, novel, patented, dextrin-colistin conjugate that can mask the toxicity of colistin; this conjugate allows controlled, enzymatically mediated dextrin degradation (unmasking) and reinstatement of colistin activity at the infected site. In the presence of amylase, the lead candidate EA-4 (1·0 mol% succinoylation, 11·2 % w/w colistin, molecular weight ~10 300 g/mol) maximally unmasked and was equally eff ective to the clinical colistin formulation against strains of multidrug resistant Acinetobacter baumannii, Escherichia coli, and Klebsiella pneumoniae (minimum inhibitory concentration ≤4 g/L), but suppression of bacterial viability was six times longer. Here we report ex-vivo and in-vivo activity, pharmacokinetics and pharmacodynamics, and toxicity.