Resistance to host-defense peptides is a critical feature of many pathogens. Previous work in the McPhee lab has demonstrated that different strains of inflammatory bowel disease-associated Escherichia coli exhibit diverse resistance to host defense peptides. The PhoPQ two-component system is a well-characterized signaling pathway that regulates the expression of genes involved in resistance to these peptides. We hypothesize that strains have an altered capacity to signal through this system, resulting in different resistance profiles. We created a promoter-GFP fusion of two PhoPQ regulated genes, pmrD and ompT, to monitor PhoPQ signaling in eight clinical isolates. Our data shows that strains have robust differences in signaling when cultured identical conditions, supporting our hypothesis. Further, our signaling match polymyxin B resistance when using the same isolates and conditions. Our data strongly suggests that strains have an altered potential to respond to environmental signals, ultimately resulting in a broad level of resistance phenotypes.