The study shows that the GraRS system in Staphylococcus aureus helps the bacteria resist the human antimicrobial peptide LL‑37 and immune cells by altering its surface charge. When GraRS is removed, the bacteria become more negatively charged, die more easily from LL‑37 and neutrophils, and cause less severe infections in mice.

Modification of teichoic acids with D-alanine by the products of the dlt operon protects Gram-positive bacteria against major antimicrobial host defense molecules such as defensins, cathelicidins, myeloperoxidase or phospholipase. The graRS regulatory genes have recently been implicated in the control of D-alanylation in Staphylococcus aureus. To determine the impact of the GraRS regulatory system on resistance to antimicrobial host defense mechanisms and virulence of S. aureus, we compared inactivation of S. aureus SA113 wild type and its isogenic graRS deletion mutant by the human cathelicidin LL-37 or human neutrophil granulocytes in vitro, and the ability to cause infection in vivo. We show here that graRS deletion considerably alters bacterial surface charge, increases susceptibility to killing by human neutrophils or the defense peptide LL-37, and attenuates virulence of S. aureus in a mouse infection model. Our results indicate that S. aureus can regulate its surface properties in order to overcome innate host defenses.