Transformation of human cathelicidin LL-37 into selective, stable, and potent antimicrobial compounds.

Authors

Guangshun Wang, University of Nebraska Medical CenterFollow
Mark L. Hanke, University of Nebraska Medical Center
Biswajit Mishra, University of Nebraska Medical CenterFollow
Tamara Lushnikova, University of Nebraska Medical CenterFollow
Cortney E. Heim, University of Nebraska Medical Center
Vinai Chittezham Thomas, University of Nebraska Medical CenterFollow
Kenneth W. Bayles, University of Nebraska Medical CenterFollow
Tammy Kielian, University of Nebraska Medical CenterFollow

Document Type

Article

Journal Title

ACS Chemical Biology

Publication Date

9-19-2014

Volume

9

Abstract

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.

MeSH Headings

Amino Acid Sequence, Animals, Antimicrobial Cationic Peptides, Catheter-Related Infections, Disease Models, Animal, Drug Design, Enterococcus faecium, Humans, Hydrophobic and Hydrophilic Interactions, Male, Methicillin-Resistant Staphylococcus aureus, Mice, Inbred C57BL, Microbial Sensitivity Tests, Molecular Sequence Data, Pseudomonas aeruginosa, Staphylococcal Infections, Staphylococcus aureus, Structure-Activity Relationship

DOI Link

10.1021/cb500475y

ISSN

1554-8937

Rights

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Recommended Citation

Wang, Guangshun; Hanke, Mark L.; Mishra, Biswajit; Lushnikova, Tamara; Heim, Cortney E.; Chittezham Thomas, Vinai; Bayles, Kenneth W.; and Kielian, Tammy, "Transformation of human cathelicidin LL-37 into selective, stable, and potent antimicrobial compounds." (2014). Journal Articles: Pathology and Microbiology. 11.
https://digitalcommons.unmc.edu/com_pathmicro_articles/11