The study looked at three natural antimicrobial peptides—IDR-1018, CATH-2, and LL‑37—to see if they could both calm inflammation and help immune cells kill Staph aureus. All three reduced inflammatory signals, but only CATH‑2 actually stopped the bacteria from growing. IDR‑1018 made immune cells take up fewer bacteria, yet it didn’t improve killing, and overall the peptides didn’t boost the cells’ natural antibacterial power. The authors suggest mixing peptides or pairing them with antibiotics for better results.

Cationic host defense peptides (HDPs) are a promising alternative to antibiotics in the fight against <i>Staphylococcus aureus</i> infections. In this study, we investigated the antibacterial and immunomodulatory properties of three HDPs namely IDR-1018, CATH-2, and LL-37. Although all three HDPs significantly inhibited LPS-induced activation of human macrophages, only CATH-2 prevented <i>S.&#xa0;aureus</i> growth. When applied to different infection models focused on intracellularly surviving bacteria, only IDR-1018 showed a consistent reduction in macrophage bacterial uptake. However, this observation did not correlate with an increase in killing the efficiency of intracellular <i>S.&#xa0;aureus</i>. Here, we conclude that despite the promising antibacterial and anti-inflammatory properties of the selected HDPs, macrophages' intrinsic antibacterial functions were not improved. Future studies should either focus on combining different HDPs or using them synergistically with other antibacterial agents to improve immune cells' efficacy against <i>S.&#xa0;aureus</i> pathogenesis.