The mammalian ionic environment dictates microbial susceptibility to antimicrobial defense peptides.

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.