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Identification and engineering of a human cathelicidin peptide LL-37mini as a novel antibiotic
1 , 2 , 2 , * 1
1  Department of Pathology and Microbiology, College of Medicine, University of Nebraska Medical Center, 985900 Nebraska Medical Center, Omaha, NE 68198-5900, USA
2  Department of Surgery-Transplant and Mary & Dick Holland Regenerative Medicine Program, College of Medicine, University of Nebraska Medical Center, Omaha, NE, 68198, USA
Academic Editor: Guangshun Wang (registering DOI)

Antimicrobial peptides are important candidates for developing new antibiotics against drug-resistant pathogens. There is a high interest in engineering human cathelicidin LL-37 to overcome its shortcomings such as high cost and lack of protease stability. Our previous studies have identified major antimicrobial peptides (SK-24, GI-20, and GF-17) as well as the smallest antibacterial peptide (KR-12) within LL-37. It is well-known that rich media (100%) could mask the activity of LL-37 against methicillin-resistant Staphylococcus aureus (MRSA). This poster found that dilution of Muller Hinton medium (MHB) led to a sensitive medium to observe LL-37 activity against MRSA. This diluted medium also allowed us to screen a library of ultrashort overlapping LL-37 peptides, leading to the identification of KR-8, which is four-residue shorter than KR-12. Based on the KR-8 template, we have engineered LL-37mini, which was potent against MRSA, Escherichia coli, and Pseudomonas aeruginosa, but was not toxic to mammalian cells. It also disrupted preformed biofilms in vitro and killed MRSA in murine wound biofilms. Consistent with membrane targeting mechanism of the peptide, S. aureus USA300 was unable to develop resistance to LL-37minin in a multiple passage experiment. The peptide is stable when made in D-amino acids. Because LL-37mini possesses numerous desired properties, it is a promising lead for developing new peptide antibiotic.

Keywords: Antibacterial susceptibility; antibiofilm; antimicrobial peptides; antimicrobial screen; LL-37mini.