The study shows that the natural antimicrobial peptide LL‑37 can kill bacteria like Staph and E. coli at normal salt levels, but only when carbonate (like bicarbonate) is present. Without carbonate, the peptide looks inactive. Bacteria adapt to carbonate‑rich environments by changing their cell wall and stress‑response genes, which makes them more vulnerable to LL‑37.

Antimicrobial peptides (AMPs) have been shown in animal and human systems to be effective natural antibiotics. However, it is unclear how they convey protection; they often appear inactive when assayed under culture conditions applied to synthetic antibiotics. This inactivation has been associated with loss of function in physiological concentrations of NaCl or serum. In this study we show that the balance of host ionic conditions dictate microbial sensitivity to AMPs. Carbonate is identified as the critical ionic factor present in mammalian tissues that imparts the ability of AMPs such as cathelicidins and defensins to kill at physiological NaCl concentrations. After adapting to carbonate-containing solutions, global changes occur in Staphylococcus aureus and Escherichia coli structure and gene expression despite no change in growth rate. Our findings show that changes in cell wall thickness and Sigma factor B expression correspond to the increased susceptibility to the AMP LL-37. These observations provide new insight into the factors involved in enabling function of innate immune effector molecules, and suggest that discovery of new antimicrobials should specifically target pathogens as they exist in the host and not the distinctly different phenotype of bacteria grown in culture broth.