Influence of Lipidation Pattern of the KR12 Fragment of Peptide LL-37 on Its Antibacterial and Hemolytic Activities.
Kamysz. Elżbieta E; Sikorska. Emilia E; Bauer. Marta M; Sikora. Karol K; Neubauer. Damian D
Key Findings
- The position and amount of lipid (fatty acid) attachment dramatically affect antibacterial activity and toxicity.
- More hydrophobic (fatty‑acid‑rich) versions tend to be more hemolytic (damage red blood cells).
- A peptide called XII, with an octanoic acid at the N‑terminus of a reversed KR12 sequence, showed the best selectivity against S. aureus (SI ≥ 21.11).
- Higher overall positive charge (+5) correlated with greater selectivity toward pathogens.
Practical Outcomes
- For DIY biohackers, this work shows that simply adding fatty acids to LL‑37 fragments can make them more or less toxic, but there’s no ready‑to‑use recipe or safe dosage for humans. It highlights the importance of charge and hydrophobic balance if you ever consider designing antimicrobial peptides, but the findings are still far from practical, clinical applications.
Summary
Scientists tweaked a small piece of the natural peptide LL‑37 by adding fatty acid groups in different spots. They found that where and how much they added these groups changed how well the peptide killed bacteria and how much it damaged red blood cells. The most promising version was a version with an octanoic acid at the start, which was good at killing Staph aureus while being less harmful to human cells, especially when the peptide carried a +5 charge.
Abstract
Contemporary medicine has been confronted by multidrug resistance. Therefore, new antibiotics are sought to alleviate the problem. In this study, we estimated the effect of the positioning and extent of lipidation (mainly octanoic acid residue) in the KR12-NH<sub>2</sub> molecule on antibacterial and hemolytic activities. The effect of the conjugation of benzoic acid derivatives (C<sub>6</sub>H<sub>5</sub>-X-COOH, where X: CH<sub>2</sub>, CH<sub>2</sub>-CH<sub>2</sub>, CH=CH, C≡C, and CH<sub>2</sub>-CH<sub>2</sub>-CH<sub>2</sub>) with the <i>N</i>-terminal part of KR12-NH<sub>2</sub> on biological activity was also studied. All analogs were tested against planktonic cells of ESKAPE bacteria and reference strains of <i>Staphylococcus aureus</i>. The effect of lipidation site on the helicity of the KR12-NH<sub>2</sub> analogs was studied using CD spectroscopy. The ability of the selected peptides to induce the aggregation of POPG liposomes was evaluated with DLS measurements. We demonstrated that both the site and extent of peptide lipidation play an essential role in the bacterial specificity of the lipopeptides. Most of the C<sub>8</sub><sup>α</sup>-KR12-NH<sub>2</sub> (<b>II</b>) analogs that were more hydrophobic than the parent compound were also more hemolytic. A similar relationship was also found between the α-helical structure content in POPC and hemolytic activity. It is worth emphasizing that in our study, the highest selectivity against <i>S. aureus</i> strains with an SI value of at least 21.11 exhibited peptide <b>XII</b> obtained by the conjugation of the octanoic acid with the <i>N</i>-terminus of retro-KR12-NH<sub>2</sub>. All lipidated analogs with the highest net charge (+5) were the most selective toward pathogens. Therefore, the overall charge of KR12-NH<sub>2</sub> analogs plays pivotal role in their biological activity.
Study Information
pubmed
2023
2023-03-13T00:00:00.000Z
10.3390/ijms24065505
11
44