Transformation of Human Cathelicidin LL-37 into Selective, Stable, and Potent Antimicrobial Compounds

This Letter reports a family of novel antimicrobial compounds obtained by combining peptide library screening with structure-based design. Library screening led to the identification of a human LL-37 peptide resistant to chymotrypsin. This d-amino-acid-containing peptide template was active against...

Full description

Saved in:
Bibliographic Details
Published in:ACS chemical biology 2014-09, Vol.9 (9), p.1997-2002
Main Authors: Wang, Guangshun, Hanke, Mark L, Mishra, Biswajit, Lushnikova, Tamara, Heim, Cortney E, Chittezham Thomas, Vinai, Bayles, Kenneth W, Kielian, Tammy
Format: Article
Language:English
Subjects:
Amino Acid Sequence
Animals
Antimicrobial Cationic Peptides - chemistry
Antimicrobial Cationic Peptides - pharmacology
Cathelicidins
Catheter-Related Infections - drug therapy
Catheter-Related Infections - microbiology
Disease Models, Animal
Drug Design
Enterococcus faecium - drug effects
Humans
Hydrophobic and Hydrophilic Interactions
Letters
Male
Methicillin-Resistant Staphylococcus aureus - drug effects
Mice, Inbred C57BL
Microbial Sensitivity Tests
Molecular Sequence Data
Pseudomonas aeruginosa - drug effects
Staphylococcal Infections - drug therapy
Staphylococcal Infections - microbiology
Staphylococcus aureus - drug effects
Staphylococcus aureus - pathogenicity
Structure-Activity Relationship
Citations: Items that this one cites
Items that cite this one
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary:This Letter reports a family of novel antimicrobial compounds obtained by combining peptide library screening with structure-based design. Library screening led to the identification of a human LL-37 peptide resistant to chymotrypsin. This d-amino-acid-containing peptide template was active against Escherichia coli but not methicillin-resistant Staphylococcus aureus (MRSA). It possesses a unique nonclassic amphipathic structure with hydrophobic defects. By repairing the hydrophobic defects, the peptide (17BIPHE2) gained activity against the ESKAPE pathogens, including Enterococcus faecium, S. aureus, Klebsiella pneumoniae, Acinetobacter baumanii, Pseudomonas aeruginosa, and Enterobacter species. In vitro, 17BIPHE2 could disrupt bacterial membranes and bind to DNA. In vivo, the peptide prevented staphylococcal biofilm formation in a mouse model of catheter-associated infection. Meanwhile, it boosted the innate immune response to further combat the infection. Because these peptides are potent, cell-selective, and stable to several proteases, they may be utilized to combat one or more ESKAPE pathogens.
ISSN:1554-8929
1554-8937
DOI:10.1021/cb500475y