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

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 <i>Escherichia coli</i> but not methicillin-resistant <i>Staphylococcus aureus</i> (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 <i>Enterococcus faecium, S. aureus, Klebsiella pneumoniae, Acinetobacter baumanii, Pseudomonas aeruginosa</i>, and <i>Enterobacter</i> species. <i>In vitro</i>, 17BIPHE2 could disrupt bacterial membranes and bind to DNA. <i>In vivo</i>, 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