The Structural Role of Lipid Domain Modifications in Antimicrobial Resistance for Salmonella Enterica Serovar Typhimurium

Abstract

Lipopolysaccharides (LPS) make up the outermost layer of Gram-negative bacterial envelopes. Bactericidal agents must either target or traverse this layer before or during primary action, it has been widely accepted that most antibiotics are either small enough to allow their diffusion through outer membrane protein channels, or sufficiently lipophilic to allow diffusion across the lipid bilayer. The two mutations of the PhoPQ regulatory system, which alters LPS structure, have been found to cause reordering of the lipid-A domains. Derived LPS domains from null and constitutive mutants were studied using Epifluorescence Microscopy (EFM), Specular X-Ray Reflectivity, and Grazing Incidence Diffraction (GIXD) and displayed an interesting response to reordering of the lipid domains. A dynamical interaction allowing interaction of the antimicrobial peptide LL-37 through incorporation into the disordered areas of the film is suggested in null mutants, whereas additions of a 4-aminoarabinose sugar group, of hydroxyl group to myristoyl residue, and of a palmitoyl group to the lipid domains displayed an ability to subvert drug traversal through a set of complex interactions, leaving the peptide only incorporated into a small portion of the outer sugar groups.