TY - JOUR

T1 - In Vitro Evaluation of the Interaction of Dextrin-Colistin Conjugates with Bacterial Lipopolysaccharide

AU - Roberts, J.L.

AU - Cattoz, B.

AU - Schweins, R.

AU - Beck, K.

AU - Thomas, D.W.

AU - Griffiths, P.C.

AU - Ferguson, E.L.

N1 - Medical Research Council (via the Severnside Alliance for Translational Research); DANSE project under NSF Award (DMR-0520547)

PY - 2016/1/5

Y1 - 2016/1/5

N2 - Dextrin-colistin conjugates have been developed with the aim of achieving reduced clinical toxicity associated with colistin, also known as polymyxin E, and improved targeting to sites of bacterial infection. This study investigated the in vitro ability of such 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 induced aggregation of LPS to form a stacked bilayer structure with characteristic dimensions, although this did not cause any substantial change in its secondary structure. In biological studies, both colistin and dextrin-colistin conjugate effectively inhibited LPS-induced hemolysis and tumor necrosis factor alpha (TNF alpha) secretion in a concentration-dependent manner, but only dextrin-colistin conjugate showed no additive toxicity at higher concentrations. This study provides the first direct structural experimental evidence for the binding of dextrin-colistin conjugates and LPS and gives insight into the mode of action of dextrin-colistin conjugates.

AB - Dextrin-colistin conjugates have been developed with the aim of achieving reduced clinical toxicity associated with colistin, also known as polymyxin E, and improved targeting to sites of bacterial infection. This study investigated the in vitro ability of such 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 induced aggregation of LPS to form a stacked bilayer structure with characteristic dimensions, although this did not cause any substantial change in its secondary structure. In biological studies, both colistin and dextrin-colistin conjugate effectively inhibited LPS-induced hemolysis and tumor necrosis factor alpha (TNF alpha) secretion in a concentration-dependent manner, but only dextrin-colistin conjugate showed no additive toxicity at higher concentrations. This study provides the first direct structural experimental evidence for the binding of dextrin-colistin conjugates and LPS and gives insight into the mode of action of dextrin-colistin conjugates.

U2 - 10.1021/acs.jmedchem.5b01521

DO - 10.1021/acs.jmedchem.5b01521

M3 - Article

VL - 59

SP - 647

EP - 654

JO - Journal of Medicinal Chemistry

JF - Journal of Medicinal Chemistry

SN - 0022-2623

IS - 2

ER -