Saheli Mitra, Mei-Tung Chen, Francisca Stedman, Jedidiah Hernandez, Grace Kumble, Xi Kang, Churan Zhang, Grace Tang, Ian Daugherty, Wanqing Liu, Jeremy Ocloo, Kevin Raphael Klucznik, Alexander Anzhi Li, Frank Heinrich, Berthony Deslouches, Stephanie Tristram-Nagle
{"title":"抗菌肽中的非天然氨基酸如何改变与脂质模型膜的相互作用?","authors":"Saheli Mitra, Mei-Tung Chen, Francisca Stedman, Jedidiah Hernandez, Grace Kumble, Xi Kang, Churan Zhang, Grace Tang, Ian Daugherty, Wanqing Liu, Jeremy Ocloo, Kevin Raphael Klucznik, Alexander Anzhi Li, Frank Heinrich, Berthony Deslouches, Stephanie Tristram-Nagle","doi":"10.1021/acs.jpcb.4c04152","DOIUrl":null,"url":null,"abstract":"<p><p>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 μM. Circular dichroism (CD) spectroscopy indicates that these peptides maintain α-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 α-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.</p>","PeriodicalId":60,"journal":{"name":"The Journal of Physical Chemistry B","volume":null,"pages":null},"PeriodicalIF":2.8000,"publicationDate":"2024-10-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"How Unnatural Amino Acids in Antimicrobial Peptides Change Interactions with Lipid Model Membranes.\",\"authors\":\"Saheli Mitra, Mei-Tung Chen, Francisca Stedman, Jedidiah Hernandez, Grace Kumble, Xi Kang, Churan Zhang, Grace Tang, Ian Daugherty, Wanqing Liu, Jeremy Ocloo, Kevin Raphael Klucznik, Alexander Anzhi Li, Frank Heinrich, Berthony Deslouches, Stephanie Tristram-Nagle\",\"doi\":\"10.1021/acs.jpcb.4c04152\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><p>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 μM. Circular dichroism (CD) spectroscopy indicates that these peptides maintain α-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 α-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.</p>\",\"PeriodicalId\":60,\"journal\":{\"name\":\"The Journal of Physical Chemistry B\",\"volume\":null,\"pages\":null},\"PeriodicalIF\":2.8000,\"publicationDate\":\"2024-10-10\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"The Journal of Physical Chemistry B\",\"FirstCategoryId\":\"1\",\"ListUrlMain\":\"https://doi.org/10.1021/acs.jpcb.4c04152\",\"RegionNum\":2,\"RegionCategory\":\"化学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"2024/9/27 0:00:00\",\"PubModel\":\"Epub\",\"JCR\":\"Q3\",\"JCRName\":\"CHEMISTRY, PHYSICAL\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"The Journal of Physical Chemistry B","FirstCategoryId":"1","ListUrlMain":"https://doi.org/10.1021/acs.jpcb.4c04152","RegionNum":2,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"2024/9/27 0:00:00","PubModel":"Epub","JCR":"Q3","JCRName":"CHEMISTRY, PHYSICAL","Score":null,"Total":0}
How Unnatural Amino Acids in Antimicrobial Peptides Change Interactions with Lipid Model Membranes.
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 μM. Circular dichroism (CD) spectroscopy indicates that these peptides maintain α-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 α-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.
期刊介绍:
An essential criterion for acceptance of research articles in the journal is that they provide new physical insight. Please refer to the New Physical Insights virtual issue on what constitutes new physical insight. Manuscripts that are essentially reporting data or applications of data are, in general, not suitable for publication in JPC B.