Abstract:
:The clinical translation of cationic α-helical antimicrobial peptides (AMPs) has been hindered by structural instability, proteolytic degradation and in vivo toxicity from nonspecific membrane lysis. Although analyses of hydrophobic content and charge distribution have informed the design of synthetic AMPs with increased potency and reduced in vitro hemolysis, nonspecific membrane toxicity in vivo continues to impede AMP drug development. Here, we analyzed a 58-member library of stapled AMPs (StAMPs) based on magainin II and applied the insights from structure-function-toxicity measurements to devise an algorithm for the design of stable, protease-resistant, potent and nontoxic StAMP prototypes. We show that a lead double-stapled StAMP named Mag(i+4)1,15(A9K,B21A,N22K,S23K) can kill multidrug-resistant Gram-negative pathogens, such as colistin-resistant Acinetobacter baumannii in a mouse peritonitis-sepsis model, without observed hemolysis or renal injury in murine toxicity studies. Inputting the amino acid sequences alone, we further generated membrane-selective StAMPs of pleurocidin, CAP18 and esculentin, highlighting the generalizability of our design platform.
journal_name
Nat Biotechnoljournal_title
Nature biotechnologyauthors
Mourtada R,Herce HD,Yin DJ,Moroco JA,Wales TE,Engen JR,Walensky LDdoi
10.1038/s41587-019-0222-zsubject
Has Abstractpub_date
2019-10-01 00:00:00pages
1186-1197issue
10eissn
1087-0156issn
1546-1696pii
10.1038/s41587-019-0222-zjournal_volume
37pub_type
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