Researchers discovered that Staph bacteria use many genes to resist the human antimicrobial peptide LL‑37 and engineered versions, and that disabling some of these genes makes the bugs more vulnerable and less able to stick together or cause infection.

<i>Staphylococcus aureus</i> is notoriously known for its rapid development of resistance to conventional antibiotics. <i>S. aureus</i> can alter its membrane composition to reduce the killing effect of antibiotics and antimicrobial peptides (AMPs). To obtain a more complete picture, this study identified the resistance genes of <i>S. aureus</i> in response to human cathelicidin LL-37 peptides by screening the Nebraska Transposon Mutant Library. In total, 24 resistant genes were identified. Among them, six mutants, including the one with the known membrane-modifying gene (<i>mprF</i>) disabled, became more membrane permeable to the LL-37 engineered peptide 17BIPHE2 than the wild type. Mass spectrometry analysis detected minimal lysyl-phosphatidylglycerol (lysylPG) from the <i>mprF</i> mutant of <i>S. aureus</i> JE2, confirming loss-of-function of this gene. Moreover, multiple mutants showed reduced surface adhesion and biofilm formation. In addition, four <i>S. aureus</i> mutants were unable to infect wax moth <i>Galleria mellonella</i>. There appears to be a connection between the ability of bacterial attachment/biofilm formation and infection. These results underscore the multiple functional roles of the identified peptide-response genes in bacterial growth, infection, and biofilm formation. Therefore, <i>S. aureus</i> utilizes a set of resistant genes to weave a complex molecular network to handle the danger posed by cationic LL-37. It appears that different genes are involved depending on the nature of antimicrobials. These resistant genes may offer a novel avenue to designing more potent antibiotics that target the Achilles heels of <i>S. aureus</i> USA300, a community-associated pathogen of great threat.