Salmonella Membrane Structural Remodeling Increases Resistance to Antimicrobial Peptide LL-37

Gram-negative bacteria are protected from their environment by an outer membrane that is primarily composed of lipopolysaccharides (LPS). Under stress, pathogenic serotypes of Salmonella enterica remodel their LPS through the PhoPQ two-component regulatory system that increases resistance to both conventional antibiotics and antimicrobial peptides (AMPs). Acquired resistance to AMPs is contrary to the established narrative that AMPs circumvent bacterial resistance by targeting the general chemical properties of membrane lipids. However, the specifc mechanisms underlying AMP resistance remain elusive. Here, we report a two-fold increase in bacteriostatic concentrations of human AMP LL-37 for Salmonella enterica with modified LPS. LPS with and without chemical modifications were isolated, and investigated by Langmuir lsotherms coupled with grazing incidence X-ray diffraction and specular X-ray reflectivity. The initial interactions between LL-37 and LPS bilayers were probed using all-atom molecular dynamics...