Group A Streptococcus (GAS) and Staphylococcus aureus (S. aureus) are pre-eminent pathogens capable of causing disease in otherwise healthy individuals. Both pathogens are associated with a wide spectrum of clinical disease ranging from relatively minor superficial infections, such as pharyngitis or impetigo, to more severe invasive disease such as bacteremia and sepsis. The increased frequency and severity of the M1T1 clone of GAS and increasing antibiotic resistance of methicillin-resistant S. aureus (MRSA) make these two pathogens excellent topics for research. Using molecular genetics, we evaluated the roles of three genes, streptococcal inhibitor of complement (sic) in GAS and aureolysin (aur) and blaI in S. aureus in regards to antimicrobial peptide (AMP) resistance and virulence. Two of these genes, sic and aur, have previously been proposed to play a role in AMP resistance and virulence through analysis of purified protein. The third gene, blaI, is a novel AMP resistance factor found through screening of a transposon library in S. aureus. In the following works, we demonstrate a contribution of SIC and BlaI to virulence in the context of the living pathogen but are unable to show a role for aureolysin

BlaI is a repressor of BlaZ, the beta-lactamase responsible for penicillin resistance in Staphylococcus aureus. Through screening a transposon library in S. aureus Newman for susceptibility to cathelicidin antimicrobial peptide, we discovered BlaI as a novel cathelicidin resistance factor. Additionally, through integrational mutagenesis in S. aureus Newman and MRSA Sanger 252 strains, we confirmed the role of BlaI in resistance to human and murine cathelidicin and showed that it contributes to virulence in human whole blood and murine infection models. We further demonstrated that BlaI could be a target for innate immune-based antimicrobial therapies; by removing BlaI through subinhibitory concentrations of 6-aminopenicillanic acid, we were able to sensitize S. aureus to LL-37 killing.