How Unnatural Amino Acids in Antimicrobial Peptides Change Interactions with Lipid Model Membranes

被引：1

作者：

Mitra, Saheli ^{[1
]}

Chen, Mei-Tung ^{[1
]}

Stedman, Francisca ^{[1
]}

Hernandez, Jedidiah ^{[1
]}

Kumble, Grace ^{[1
]}

Kang, Xi ^{[1
]}

Zhang, Churan ^{[1
]}

Tang, Grace ^{[1
]}

Daugherty, Ian ^{[1
]}

Liu, Wanqing ^{[1
]}

Ocloo, Jeremy ^{[1
]}

Klucznik, Kevin Raphael ^{[1
]}

Li, Alexander Anzhi ^{[1
]}

Heinrich, Frank ^{[1
,2
]}

Deslouches, Berthony ^{[3
]}

Tristram-Nagle, Stephanie ^{[1
]}

机构：

[1] Carnegie Mellon Univ, Phys Dept, Biol Phys Grp, Pittsburgh, PA 15213 USA

[2] NIST, Ctr Neutron Res, Gaithersburg, MD 20899 USA

[3] Univ Pittsburgh, Dept Environm & Occupat Hlth, Pittsburgh, PA 15261 USA

来源：

JOURNAL OF PHYSICAL CHEMISTRY B | 2024年 / 128卷 / 40期

基金：

美国国家科学基金会; 美国国家卫生研究院;

关键词：

FUNCTIONAL-PROPERTIES; SECONDARY STRUCTURE; TRYPTOPHAN; MECHANISM; INSERTION; MAGAININ; DESIGN; GENERATION; PARAMETERS; RESISTANCE;

D O I：

10.1021/acs.jpcb.4c04152

中图分类号：

O64 [物理化学（理论化学）、化学物理学];

学科分类号：

070304 ; 081704 ;

摘要：

This study investigates the potential of antimicrobial peptides (AMPs) as alternatives to combat antibiotic resistance, with a focus on two AMPs containing unnatural amino acids (UAAs), E2-53R (16 AAs) and LE-54R (14 AAs). In both peptides, valine is replaced by norvaline (Nva), and tryptophan is replaced by 1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid (Tic). Microbiological studies reveal their potent activity against both Gram-negative (G(-)) and Gram-positive (G(+)) bacteria without any toxicity to eukaryotic cells at test concentrations up to 32 mu M. Circular dichroism (CD) spectroscopy indicates that these peptides maintain alpha-helical structures when interacting with G(-) and G(+) lipid model membranes (LMMs), a feature linked to their efficacy. X-ray diffuse scattering (XDS) demonstrates a softening of G(-), G(+) and eukaryotic (Euk33) LMMs and a nonmonotonic decrease in chain order as a potential determinant for bacterial membrane destabilization. Additionally, XDS finds a significant link between both peptides' interfacial location in G(-) and G(+) LMMs and their efficacy. Neutron reflectometry (NR) confirms the AMP locations determined using XDS. Lack of toxicity in eukaryotic cells may be related to their loss of alpha-helicity and their hydrocarbon location in Euk33 LMMs. Both AMPs with UAAs offer a novel strategy to wipe out antibiotic-resistant strains while maintaining human cells. These findings are compared with previously published data on E2-35, which consists of the natural amino acids arginine, tryptophan, and valine.

引用

页码：9772 / 9784

页数：13