Repurposing a peptide toxin from wasp venom into antiinfectives with dual antimicrobial and immunomodulatory properties
© 2020 National Academy of Sciences. All rights reserved. Novel antibiotics are urgently needed to combat multidrug-resistant pathogens. Venoms represent previously untapped sources of novel drugs. Here we repurposed mastoparan-L, the toxic active principle derived from the venom of the wasp Vespula...
| Main Authors: | , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Proceedings of the National Academy of Sciences
2021
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| Online Access: | https://hdl.handle.net/1721.1/134150 |
| _version_ | 1811097990381699072 |
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| author | Silva, Osmar N Torres, Marcelo DT Cao, Jicong Alves, Elaine SF Rodrigues, Leticia V Resende, Jarbas M Lião, Luciano M Porto, William F Fensterseifer, Isabel CM Lu, Timothy K Franco, Octavio L de la Fuente-Nunez, Cesar |
| author2 | Massachusetts Institute of Technology. Synthetic Biology Center |
| author_facet | Massachusetts Institute of Technology. Synthetic Biology Center Silva, Osmar N Torres, Marcelo DT Cao, Jicong Alves, Elaine SF Rodrigues, Leticia V Resende, Jarbas M Lião, Luciano M Porto, William F Fensterseifer, Isabel CM Lu, Timothy K Franco, Octavio L de la Fuente-Nunez, Cesar |
| author_sort | Silva, Osmar N |
| collection | MIT |
| description | © 2020 National Academy of Sciences. All rights reserved. Novel antibiotics are urgently needed to combat multidrug-resistant pathogens. Venoms represent previously untapped sources of novel drugs. Here we repurposed mastoparan-L, the toxic active principle derived from the venom of the wasp Vespula lewisii, into synthetic antimicrobials. We engineered within its N terminus a motif conserved among natural peptides with potent immunomodulatory and antimicrobial activities. The resulting peptide, mast-MO, adopted an α-helical structure as determined by NMR, exhibited increased antibacterial properties comparable to standard-of-care antibiotics both in vitro and in vivo, and potentiated the activity of different classes of antibiotics. Mechanism-of-action studies revealed that mast-MO targets bacteria by rapidly permeabilizing their outer membrane. In animal models, the peptide displayed direct antimicrobial activity, led to enhanced ability to attract leukocytes to the infection site, and was able to control inflammation. Permutation studies depleted the remaining toxicity of mast-MO toward human cells, yielding derivatives with antiinfective activity in animals. We demonstrate a rational design strategy for repurposing venoms into promising antimicrobials. |
| first_indexed | 2024-09-23T17:08:13Z |
| format | Article |
| id | mit-1721.1/134150 |
| institution | Massachusetts Institute of Technology |
| language | English |
| last_indexed | 2024-09-23T17:08:13Z |
| publishDate | 2021 |
| publisher | Proceedings of the National Academy of Sciences |
| record_format | dspace |
| spelling | mit-1721.1/1341502023-12-06T18:35:09Z Repurposing a peptide toxin from wasp venom into antiinfectives with dual antimicrobial and immunomodulatory properties Silva, Osmar N Torres, Marcelo DT Cao, Jicong Alves, Elaine SF Rodrigues, Leticia V Resende, Jarbas M Lião, Luciano M Porto, William F Fensterseifer, Isabel CM Lu, Timothy K Franco, Octavio L de la Fuente-Nunez, Cesar Massachusetts Institute of Technology. Synthetic Biology Center Massachusetts Institute of Technology. Department of Biological Engineering Massachusetts Institute of Technology. Department of Electrical Engineering and Computer Science Massachusetts Institute of Technology. Research Laboratory of Electronics Massachusetts Institute of Technology. Department of Biology © 2020 National Academy of Sciences. All rights reserved. Novel antibiotics are urgently needed to combat multidrug-resistant pathogens. Venoms represent previously untapped sources of novel drugs. Here we repurposed mastoparan-L, the toxic active principle derived from the venom of the wasp Vespula lewisii, into synthetic antimicrobials. We engineered within its N terminus a motif conserved among natural peptides with potent immunomodulatory and antimicrobial activities. The resulting peptide, mast-MO, adopted an α-helical structure as determined by NMR, exhibited increased antibacterial properties comparable to standard-of-care antibiotics both in vitro and in vivo, and potentiated the activity of different classes of antibiotics. Mechanism-of-action studies revealed that mast-MO targets bacteria by rapidly permeabilizing their outer membrane. In animal models, the peptide displayed direct antimicrobial activity, led to enhanced ability to attract leukocytes to the infection site, and was able to control inflammation. Permutation studies depleted the remaining toxicity of mast-MO toward human cells, yielding derivatives with antiinfective activity in animals. We demonstrate a rational design strategy for repurposing venoms into promising antimicrobials. 2021-10-27T19:58:21Z 2021-10-27T19:58:21Z 2020 2021-01-28T19:37:56Z Article http://purl.org/eprint/type/JournalArticle https://hdl.handle.net/1721.1/134150 en 10.1073/PNAS.2012379117 Proceedings of the National Academy of Sciences of the United States of America Article is made available in accordance with the publisher's policy and may be subject to US copyright law. Please refer to the publisher's site for terms of use. application/pdf Proceedings of the National Academy of Sciences PNAS |
| spellingShingle | Silva, Osmar N Torres, Marcelo DT Cao, Jicong Alves, Elaine SF Rodrigues, Leticia V Resende, Jarbas M Lião, Luciano M Porto, William F Fensterseifer, Isabel CM Lu, Timothy K Franco, Octavio L de la Fuente-Nunez, Cesar Repurposing a peptide toxin from wasp venom into antiinfectives with dual antimicrobial and immunomodulatory properties |
| title | Repurposing a peptide toxin from wasp venom into antiinfectives with dual antimicrobial and immunomodulatory properties |
| title_full | Repurposing a peptide toxin from wasp venom into antiinfectives with dual antimicrobial and immunomodulatory properties |
| title_fullStr | Repurposing a peptide toxin from wasp venom into antiinfectives with dual antimicrobial and immunomodulatory properties |
| title_full_unstemmed | Repurposing a peptide toxin from wasp venom into antiinfectives with dual antimicrobial and immunomodulatory properties |
| title_short | Repurposing a peptide toxin from wasp venom into antiinfectives with dual antimicrobial and immunomodulatory properties |
| title_sort | repurposing a peptide toxin from wasp venom into antiinfectives with dual antimicrobial and immunomodulatory properties |
| url | https://hdl.handle.net/1721.1/134150 |
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