Laboratory of Chemistry of Biological Macromolecules, Department of Molecular Biotechnology, Faculty of Chemistry, University of Gdańsk, 80-308 Gdańsk, Poland.
Laboratory of Structural Studies of Biopolymers, Department of Organic Chemistry, Faculty of Chemistry, University of Gdańsk, 80-308 Gdańsk, Poland.
Int J Mol Sci. 2023 Mar 13;24(6):5505. doi: 10.3390/ijms24065505.
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 molecule on antibacterial and hemolytic activities. The effect of the conjugation of benzoic acid derivatives (CH-X-COOH, where X: CH, CH-CH, CH=CH, C≡C, and CH-CH-CH) with the -terminal part of KR12-NH on biological activity was also studied. All analogs were tested against planktonic cells of ESKAPE bacteria and reference strains of . The effect of lipidation site on the helicity of the KR12-NH 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-KR12-NH () 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 strains with an SI value of at least 21.11 exhibited peptide obtained by the conjugation of the octanoic acid with the -terminus of retro-KR12-NH. All lipidated analogs with the highest net charge (+5) were the most selective toward pathogens. Therefore, the overall charge of KR12-NH analogs plays pivotal role in their biological activity.
当代医学面临着多药耐药性的问题。因此，人们正在寻找新的抗生素来缓解这一问题。在这项研究中，我们评估了 KR12-NH 分子中定位和脂质化程度（主要是辛酸残基）对抗菌和溶血活性的影响。我们还研究了苯甲酸衍生物（CH-X-COOH，其中 X：CH、CH-CH、CH=CH、C≡C 和 CH-CH-CH）与 KR12-NH 末端部分缀合对生物活性的影响。所有类似物均针对 ESKAPE 细菌的浮游细胞和参考菌株进行了测试。使用 CD 光谱研究了脂质化位点对 KR12-NH 类似物螺旋性的影响。用 DLS 测量评估了所选肽诱导 POPG 脂质体聚集的能力。我们证明，肽的脂质化位点和程度对脂肽的细菌特异性起着重要作用。大多数比母体化合物更疏水的 C-KR12-NH（）类似物也具有更高的溶血活性。在 POPC 中的α-螺旋结构含量与溶血活性之间也发现了类似的关系。值得强调的是，在我们的研究中，对具有至少 21.11 的 SI 值的 菌株表现出最高选择性的肽是通过将辛酸与 retro-KR12-NH 的末端缀合而获得的肽。所有带最高净电荷（+5）的脂质化类似物对病原体的选择性最高。因此，KR12-NH 类似物的总电荷在其生物学活性中起着关键作用。
