Scientists made a new hybrid peptide called TAT‑KR‑12 that can slip into human cells and kill the bad bacteria Staphylococcus aureus, which often hides inside cells and causes hard‑to‑treat infections. In lab dishes and in mice, this peptide cleared the bacteria, reduced inflammation, and didn’t hurt the host cells.

<i>Staphylococcus aureus</i> is a primary pathogen responsible for causing postoperative infections as it survives and persists in host cells, including osteoblasts and macrophages. These cells then serve as reservoirs resulting in chronic infections. Most traditional antibiotics have poor effects on intracellular <i>S.&#xa0;aureus</i> because they cannot enter the cell. Herein, a cell-penetrating peptide TAT-KR-12 was derived from the trans-activating transcription (TAT) peptide and KR-12 (residues 18-29 of human cathelicidin LL-37). The TAT acts as a "trojan horse" to deliver KR-12 peptide into the cells to kill <i>S.&#xa0;aureus</i>. Moreover, effective antibacterial properties and biocompatibility were observed <i>in vitro</i>, demonstrating that TAT-KR-12 is effective not only in eliminating planktonic <i>S.&#xa0;aureus</i>, but also in eliminating intracellular <i>S.&#xa0;aureus</i> cells <i>in vitro</i>. TAT-KR-12, as with LL-37, also elicits strong anti-inflammatory activities in LPS-stimulated macrophages, as demonstrated by significant inhibition of NO, TNF-&#x3b1;, and IL-1&#x3b2; expression and secretion from LPS-stimulated RAW264.7 cells. In the subcutaneous infection mouse model of planktonic and intracellular infections, the growth of <i>S.&#xa0;aureus</i><i>in vivo</i> is evidently inhibited without cytotoxicity. These results suggest that the novel antimicrobial TAT-KR-12 may prove to be an effective treatment option to overcome antibiotic resistance caused by intracellular bacterial infections.