INVESTIGADORES
DUPUY Fernando Gabriel
congresos y reuniones científicas
Título:
Selective Interaction of Colistin with Lipid Model Membranes
Autor/es:
DUPUY, FERNANDO G.; PAGANO, ISABELLA; ANDENORO, KATHRYN; PERALTA, MARIA F.; ELHADY, YASMENE; TRISTRAM-NAGLE, STEPHANIE
Reunión:
Congreso; 62th Annual Meeting Biophysical Society; 2018
Institución organizadora:
Biophysical Society
Resumen:
Although colistin?s clinical use is limited due to nephrotoxicity, colistin is considered an antibiotic of last resort since it is used to treat patients in- fected with multi-drug resistant bacteria. In an effort to provide molecular details about colistin?s ability to kill Gram-negative (G(-)) but not Gram- positive (G(þ)) bacteria, we investigated the biophysics of interaction be- tween colistin and lipid mixtures mimicking the cytoplasmic membrane of G(þ), G(-) bacteria as well as eukaryotic cells. Two different models of G(-) outer membrane (OM) were assayed: lipid A with two deoxy- manno-octulosonyl sugar residues (KDO2) and Escherichia coli lipopoly- saccharide (LPS) mixed with dilaurylphosphatidylglycerol. We used circular dichroism and X-ray diffuse scattering at low and wide angle in stacked multilayered samples, and neutron reflectivity (NR) of single, teth- ered bilayers mixed with colistin. We found no differences in secondary structure when colistin was bound to G(-) vs G(þ) membrane mimics, ruling out a protein conformational change as the cause of this difference. However, bending modulus KC perturbation was quite irregular for G(-) IM, where colistin produced a softening of membranes at intermediate lip- id:peptide molar ratio but stiffening at lower and higher peptide concentra- tions, while in G(þ) and eukaryotic mimics there was only a slight softening. Acyl chain order in G(-) was perturbed similarly to KC. In G(þ) there was only a slight softening and disordering effect, while in OM mimics, there was a slight stiffening and ordering of both membranes with increasing colistin. X-ray and NR structural results reveal colistin par- titions deepest into the hydrocarbon interior in G(-) membranes, but re- mains in the headgroup region in G(þ), OM and eukaryotic mimics. It is possible that domain formation is responsible for the erratic response of G(-) inner membranes to colistin and for its deeper penetration, which could increase membrane permeability.