Mechanistic Insights into Human Antimicrobial Peptide-Induced Activation of a Broadly Conserved Bacterial Signaling System.

Antimicrobial peptides (AMPs) represent a promising class of therapeutics against bacterial pathogens. While their direct bactericidal mechanisms are well-characterized, how bacteria sense and respond to these peptides at sublethal concentrations remains poorly understood. Here, we investigate the activation of the PhoQ-PhoP signaling system by the human cathelicidin LL-37 and its derivatives (KR-12 and RI-10). We demonstrate that these peptides exhibit variable antimicrobial potency but surprisingly similar abilities to activate the PhoQ-PhoP pathway, indicating that signaling function is separable from bactericidal activity. Notably, sublethal concentrations of these peptides induce significant cell elongation, a phenotype dependent on PhoQ and mediated by the upregulation of QueE, which interferes with bacterial cell division. Contrary to the previous model suggesting peptides activate PhoQ passively by displacing its inhibitor MgrB, we observed enhanced cell elongation in strains across all tested peptides, including RI-10, lacking antibacterial activity. Our findings suggest peptides actively stimulate PhoQ through a mechanism independent of MgrB dissociation, providing a more refined understanding of the peptide signaling through the PhoQ- PhoP system. These insights into bacterial adaptation mechanisms against host-derived peptides may guide the development of peptide therapeutics with enhanced efficacy against drug-resistant pathogens.