Repurposing a peptide toxin from wasp venom into antiinfectives with dual antimicrobial and immunomodulatory properties
| Autor: | William F. Porto, Elaine S. F. Alves, Isabel C. M. Fensterseifer, Osmar N. Silva, Marcelo D. T. Torres, Jicong Cao, Leticia V. Rodrigues, Octavio L. Franco, Jarbas M. Resende, Luciano M. Lião, Cesar de la Fuente-Nunez, Timothy K. Lu |
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| Jazyk: | angličtina |
| Rok vydání: | 2020 |
| Předmět: |
Pore Forming Cytotoxic Proteins
medicine.drug_class Antibiotics Antimicrobial peptides Drug Evaluation Preclinical Peptide Venom Bacteremia Wasp Venoms Microbial Sensitivity Tests Microbiology Mice In vivo medicine Animals Humans chemistry.chemical_classification Multidisciplinary Rational design Correction Biological Sciences Antimicrobial In vitro HEK293 Cells chemistry Drug Design |
| Zdroj: | Proc Natl Acad Sci U S A |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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