Maturana P, Martinez M, Noguera M E, Santos N C, Disalvo E A, Semorile L, Maffia P C, Hollmann A
Laboratory of Biointerfaces and Biomimetic Systems- CITSE-National University of Santiago del Estero, Santiago del Estero and CONICET, Argentina.
Laboratory of Molecular Microbiology, Institute of Basic and Applied Microbiology, University of Quilmes, B1876BXD Bernal, Argentina; Concejo Nacional de Investigaciones Científicas y Técnicas (CONICET).
Colloids Surf B Biointerfaces. 2017 May 1;153:152-159. doi: 10.1016/j.colsurfb.2017.02.003. Epub 2017 Feb 13.
Antimicrobial peptides (AMPs) are small cationic molecules that display antimicrobial activity against a wide range of bacteria, fungi and viruses. For an AMP to be considered as a therapeutic option, it must have not only potent antibacterial properties but also low hemolytic and cytotoxic activities [1]. Even though many studies have been conducted in order to correlate the antimicrobial activity with affinity toward model lipid membranes, the use of these membranes to explain cytotoxic effects (especially hemolysis) has been less explored. In this context, we studied lipid selectivity in two related novel AMPs, peptide 6 (P6) and peptide 6.2 (P6.2). Each peptide was designed from a previously reported AMP, and specific amino acid replacements were performed in an attempt to shift their hydrophobic moment or net charge. P6 showed no antimicrobial activity and high hemolytic activity, and P6.2 exhibited good antibacterial and low hemolytic activity. Using both peptides as a model we correlated the affinity toward membranes of different lipid composition and the antimicrobial and hemolytic activities. Our results from surface pressure and zeta potential assays showed that P6.2 exhibited a higher affinity and faster binding kinetic toward PG-containing membranes, while P6 showed this behavior for pure PC membranes. The final position and structure of P6.2 into the membrane showed an alpha-helix conversion, resulting in a parallel alignment with the Trps inserted into the membrane. On the other hand, the inability of P6 to adopt an amphipathic structure, plus its lower affinity toward PG-containing membranes seem to explain its poor antimicrobial activity. Regarding erythrocyte interactions, P6 showed the highest affinity toward erythrocyte membranes, resulting in an increased hemolytic activity. Overall, our data led us to conclude that affinity toward negatively charged lipids instead of zwitterionic ones seems to be a key factor that drives from hemolytic to antimicrobial activity.
抗菌肽（AMPs）是一类小分子阳离子物质，对多种细菌、真菌和病毒具有抗菌活性。要将一种抗菌肽视为一种治疗选择，它不仅必须具有强大的抗菌特性，还必须具有低溶血和细胞毒性活性[1]。尽管已经进行了许多研究，以将抗菌活性与对模型脂质膜的亲和力相关联，但利用这些膜来解释细胞毒性作用（尤其是溶血作用）的研究较少。在此背景下，我们研究了两种相关的新型抗菌肽肽6（P6）和肽6.2（P6.2）的脂质选择性。每种肽都是根据先前报道的抗菌肽设计的，并进行了特定的氨基酸替换，试图改变它们的疏水矩或净电荷。P6没有抗菌活性，但具有高溶血活性，而P6.2表现出良好的抗菌活性和低溶血活性。以这两种肽为模型，我们将对不同脂质组成的膜的亲和力与抗菌和溶血活性相关联。我们通过表面压力和zeta电位测定得到的结果表明，P6.2对含PG的膜表现出更高的亲和力和更快的结合动力学，而P6对纯PC膜表现出这种行为。P6.2在膜中的最终位置和结构显示出α-螺旋转变，导致与插入膜中的色氨酸平行排列。另一方面，P6无法形成两亲结构，加上其对含PG膜的亲和力较低，似乎可以解释其较差的抗菌活性。关于红细胞相互作用，P6对红细胞膜表现出最高的亲和力，导致溶血活性增加。总体而言，我们的数据使我们得出结论，对带负电荷脂质而非两性离子脂质的亲和力似乎是从溶血活性转变为抗菌活性的关键因素。
