Senetra Alexandria S, Necelis Matthew R, Caputo Gregory A
Department of Chemistry and Biochemistry, Rowan University, Glassboro, NJ 08028, U.S.A.
Department of Molecular and Cellular Biosciences, Rowan University, Glassboro, NJ 08028, U.S.A.
Pept Sci (Hoboken). 2020 May;112(3). doi: 10.1002/pep2.24162. Epub 2020 Mar 31.
Naturally derived antimicrobial peptides have been an area of great interest because of high selectivity against bacterial targets over host cells and the limited development of bacterial resistance to these molecules throughout evolution. There are also a significant number of venom-derived peptides that exhibit antimicrobial activity in addition to activity against mammals or other organisms. Many venom peptides share the same net cationic, amphiphilic nature as host-defense peptides, making them an attractive target for development as potential antibacterial agents. The peptide ponericin L1 derived from was used as a model to investigate the role of cationic residues and net charge on peptide activity. Using a combination of spectroscopic and microbiological approaches, the role of cationic residues and net charge on antibacterial activity, lipid bilayer interactions, and bilayer and membrane permeabilization were investigated. The L1 peptide and derivatives all showed enhanced binding to lipid vesicles containing anionic lipids, but still bound to zwitterionic vesicles. None of the derivatives were especially effective at permeabilizing lipid bilayers in model vesicles, in-tact , or human red blood cells. Taken together the results indicate that the lack of facial amphiphilicity regarding charge segregation may impact the ability of the L1 peptides to effectively permeabilize bilayers despite effective binding. Additionally, increasing the net charge of the peptide by replacing the lone anionic residue with either Gln or Lys dramatically improved efficacy against several bacterial strains without increasing hemolytic activity.
天然衍生的抗菌肽一直是一个备受关注的领域，因为它们对细菌靶点的选择性高于宿主细胞，并且在整个进化过程中细菌对这些分子产生耐药性的情况有限。此外，还有大量源自毒液的肽，除了对哺乳动物或其他生物体具有活性外，还表现出抗菌活性。许多毒液肽与宿主防御肽具有相同的净阳离子、两亲性性质，这使得它们成为开发潜在抗菌剂的有吸引力的目标。从[来源]衍生的肽波那菌素L1被用作模型，以研究阳离子残基和净电荷对肽活性的作用。通过结合光谱学和微生物学方法，研究了阳离子残基和净电荷在抗菌活性、脂质双层相互作用以及双层和膜通透性方面的作用。L1肽及其衍生物均显示出与含有阴离子脂质的脂质囊泡的结合增强，但仍与两性离子囊泡结合。在模型囊泡、完整的[细胞类型]或人类红细胞中，没有一种衍生物在使脂质双层通透方面特别有效。综合结果表明，尽管电荷分离缺乏表面两亲性，但L1肽有效结合的情况下，可能会影响其有效通透双层膜的能力。此外，通过用Gln或Lys取代唯一的阴离子残基来增加肽的净电荷，可显著提高对几种细菌菌株的疗效，而不会增加溶血活性。
