Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 117, Issue 43, Pages 26936-26945Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.2012379117
Keywords
venoms; antimicrobial peptides; immunomodulatory peptides; antiinfectives; structure-activity relationship
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Funding
- AIChE Foundation
- Institute for Diabetes, Obesity, and Metabolism
- Penn Mental Health AIDS Research Center of the University of Pennsylvania
- Fundacao de Amparo a Pesquisa do Estado de Goias [201710267000062]
- Comissao de Aperfeicoamento de Pessoal de Nival Superior
- Conselho Nacional de Pesquisas [407181/2013-0]
- Financiadora de Estudos e Projetos
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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 a-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. Mechanismof-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.
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