Scientists added different fatty‑acid tails to a short piece of the natural antimicrobial peptide LL‑37 (called KR12). Adding a medium‑length tail (about 8 carbons) made the peptide kill drug‑resistant bacteria at low doses, but longer tails (like 14 carbons) caused the peptide to clump together and become less effective. All the fatty‑acid‑modified versions were also more toxic to human cells, meaning safety is a big concern.

An increasing number of multidrug-resistant pathogens is a serious problem of modern medicine and new antibiotics are highly demanded. In this study, different n-alkyl acids (C₂-C₁₄) and aromatic acids (benzoic and <i>trans</i>-cinnamic) were conjugated to the <i>N</i>-terminus of KR12 amide. The effect of this modification on antimicrobial activity (ESKAPE bacteria and biofilm of <i>Staphylococcus aureus</i>) and cytotoxicity (human red blood cells and HaCaT cell line) was examined. The effect of lipophilic modifications on helicity was studied by CD spectroscopy, whereas peptide self-assembly was studied by surface tension measurements and NMR spectroscopy. As shown, conjugation of the KR12-NH₂ peptide with C₄-C₁₄ fatty acid chains enhanced the antimicrobial activity with an optimum demonstrated by C₈-KR12-NH₂ (MIC 1-4 &#x3bc;g/mL against ESKAPE strains; MBEC of <i>S. aureus</i> 4-16 &#x3bc;g/mL). Correlation between antimicrobial activity and self-assembly behavior of C₁₄-KR12-NH₂ and C₈-KR12-NH₂ has shown that the former self-assembled into larger aggregated structures, which reduced its antimicrobial activity. In conclusion, <i>N</i>-terminal modification can enhance antimicrobial activity of KR12-NH₂; however, at the same time, the cytotoxicity increases. It seems that the selectivity against pathogens over human cells can be achieved through conjugation of peptide <i>N</i>-terminus with appropriate n-alkyl fatty and aromatic acids.