Abstract:
: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.
journal_name
Proc Natl Acad Sci U S Aauthors
Silva ON,Torres MDT,Cao J,Alves ESF,Rodrigues LV,Resende JM,Lião LM,Porto WF,Fensterseifer ICM,Lu TK,Franco OL,de la Fuente-Nunez Cdoi
10.1073/pnas.2012379117subject
Has Abstractpub_date
2020-10-27 00:00:00pages
26936-26945issue
43eissn
0027-8424issn
1091-6490pii
2012379117journal_volume
117pub_type
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