Polymyxins slow down lateral diffusion of proteins and lipopolysaccharide in the E. coli outer membrane

Abstract

Polymyxins are often administered as last resort antibiotics for Gram-negative bacterial infections. However, given unwanted side-effects, efficacy and recent reports of resistance against polymyxins, there is an urgency to develop alternatives. This necessitates an understanding of how polymyxins associate with and translocate across the formidable permeability barrier of the Gram-negative bacterial outer membrane. We employ multi-scale molecular simulations to explore the initial association of polymyxin B1 using E. coli outer membrane models that incorporate the latest details of supramolecular lattice networks formed by lipids and native proteins. We show that polymyxin molecules attach to the outer membrane surface, reducing the lateral displacement of proteins and lipopolysaccharides, and polymyxins often associate into large protein-polymyxin aggregates that link individual proteins. Furthermore, we provide atomistic resolution insights into the interaction network between proteins, lipopolysaccharides and polymyxins that lead to the reduced lateral mobility of proteins and lipopolysaccharides in the E. coli outer membrane.