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Lipidated variants of the antimicrobial peptide nisin produced via incorporation of methionine analogs for click chemistry show improved bioactivity
The increase in antibiotic resistance calls for accelerated molecular engineering strategies to diversify natural products for drug discovery. The incorporation of non-canonical amino acids (ncAAs) is an elegant strategy for this purpose, offering a diverse pool of building blocks to introduce desir...
Autores principales: | , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
American Society for Biochemistry and Molecular Biology
2023
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10404616/ https://www.ncbi.nlm.nih.gov/pubmed/37209826 http://dx.doi.org/10.1016/j.jbc.2023.104845 |
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author | Guo, Longcheng Wang, Chenhui Broos, Jaap Kuipers, Oscar P. |
author_facet | Guo, Longcheng Wang, Chenhui Broos, Jaap Kuipers, Oscar P. |
author_sort | Guo, Longcheng |
collection | PubMed |
description | The increase in antibiotic resistance calls for accelerated molecular engineering strategies to diversify natural products for drug discovery. The incorporation of non-canonical amino acids (ncAAs) is an elegant strategy for this purpose, offering a diverse pool of building blocks to introduce desired properties into antimicrobial lanthipeptides. We here report an expression system using Lactococcus lactis as a host for non-canonical amino acid incorporation with high efficiency and yield. We show that incorporating the more hydrophobic analog ethionine (instead of methionine) into nisin improves its bioactivity against several Gram-positive strains we tested. New-to-nature variants were further created by click chemistry. By azidohomoalanine (Aha) incorporation and subsequent click chemistry, we obtained lipidated variants at different positions in nisin or in truncated nisin variants. Some of them show improved bioactivity and specificity against several pathogenic bacterial strains. These results highlight the ability of this methodology for lanthipeptide multi-site lipidation, to create new-to-nature antimicrobial products with diverse features, and extend the toolbox for (lanthi)peptide drug improvement and discovery. |
format | Online Article Text |
id | pubmed-10404616 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2023 |
publisher | American Society for Biochemistry and Molecular Biology |
record_format | MEDLINE/PubMed |
spelling | pubmed-104046162023-08-08 Lipidated variants of the antimicrobial peptide nisin produced via incorporation of methionine analogs for click chemistry show improved bioactivity Guo, Longcheng Wang, Chenhui Broos, Jaap Kuipers, Oscar P. J Biol Chem Research Article The increase in antibiotic resistance calls for accelerated molecular engineering strategies to diversify natural products for drug discovery. The incorporation of non-canonical amino acids (ncAAs) is an elegant strategy for this purpose, offering a diverse pool of building blocks to introduce desired properties into antimicrobial lanthipeptides. We here report an expression system using Lactococcus lactis as a host for non-canonical amino acid incorporation with high efficiency and yield. We show that incorporating the more hydrophobic analog ethionine (instead of methionine) into nisin improves its bioactivity against several Gram-positive strains we tested. New-to-nature variants were further created by click chemistry. By azidohomoalanine (Aha) incorporation and subsequent click chemistry, we obtained lipidated variants at different positions in nisin or in truncated nisin variants. Some of them show improved bioactivity and specificity against several pathogenic bacterial strains. These results highlight the ability of this methodology for lanthipeptide multi-site lipidation, to create new-to-nature antimicrobial products with diverse features, and extend the toolbox for (lanthi)peptide drug improvement and discovery. American Society for Biochemistry and Molecular Biology 2023-05-19 /pmc/articles/PMC10404616/ /pubmed/37209826 http://dx.doi.org/10.1016/j.jbc.2023.104845 Text en © 2023 The Authors https://creativecommons.org/licenses/by-nc-nd/4.0/This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/). |
spellingShingle | Research Article Guo, Longcheng Wang, Chenhui Broos, Jaap Kuipers, Oscar P. Lipidated variants of the antimicrobial peptide nisin produced via incorporation of methionine analogs for click chemistry show improved bioactivity |
title | Lipidated variants of the antimicrobial peptide nisin produced via incorporation of methionine analogs for click chemistry show improved bioactivity |
title_full | Lipidated variants of the antimicrobial peptide nisin produced via incorporation of methionine analogs for click chemistry show improved bioactivity |
title_fullStr | Lipidated variants of the antimicrobial peptide nisin produced via incorporation of methionine analogs for click chemistry show improved bioactivity |
title_full_unstemmed | Lipidated variants of the antimicrobial peptide nisin produced via incorporation of methionine analogs for click chemistry show improved bioactivity |
title_short | Lipidated variants of the antimicrobial peptide nisin produced via incorporation of methionine analogs for click chemistry show improved bioactivity |
title_sort | lipidated variants of the antimicrobial peptide nisin produced via incorporation of methionine analogs for click chemistry show improved bioactivity |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10404616/ https://www.ncbi.nlm.nih.gov/pubmed/37209826 http://dx.doi.org/10.1016/j.jbc.2023.104845 |
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