Dextrin-colistin conjugates have been developed with the aim of reducing clinical toxicity associated with colistin and improving targeting to sites of bacterial infection. This study investigated the in vitro ability of these dextrin-colistin conjugates to bind and modulate bacterial lipopolysaccharide (LPS), and how this binding affects its biological activity. These results showed that colistin, and ‘amylase-activated’ dextrin-colistin conjugate to a lesser extent, bound to LPS and induced significant conformational changes to its structure. In biological studies, both colistin and dextrin-colistin conjugate effectively inhibited LPS-induced hemolysis and TNFα secretion in a concentration-dependent manner, but only dextrin-colistin conjugate did not cause additive toxicity at higher concentrations. This study provides the first direct structural experimental evidence for the binding of dextrin-colistin conjugates and LPS, providing insight into the mode of action of dextrin-colistin conjugates.
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