Repurposing a peptide toxin from wasp venom into antiinfectives with dual antimicrobial and immunomodulatory properties
Name
26936.full.pdf
Description
Published version
Size
1.63 MB
Format
Adobe PDF
Checksum (MD5)
29ab272c4af363ed5fd33b71b93f43d8
Author(s)
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
Date Issued
2020
Journal
Proceedings of the National Academy of Sciences of the United States of America
Publisher
Proceedings of the National Academy of Sciences
Version
Final published version
Abstract
© 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.
MIT Department
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
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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.
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DOI of Published Version
https://doi.org/10.1073/PNAS.2012379117
