Design potent peptide antibiotics against the ESKAPE pathogens based on human antimicrobial peptide LL-37

Abstract

Antimicrobial peptides (AMPs) are key components of innate immune systems. Because of their lasting potency, AMPs are regarded as useful candidates for developing the next generation of antimicrobials to meet the challenge of antibiotic resistance. According to CDC, 90% infections are related to the difficult-to-treat ESKAPE pathogens, including Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, and Enterobacter species. In this lecture, I will discuss peptide design based on human cathelicidin LL-37, one of the best-studied host defense peptides. Both synthetic peptide library and structure-based design methods were utilized to identify the active regions. Although challenging, the determination of the 3D structure of LL-37 enabled the identification of the core antimicrobial region in 2006. However, the minimal region of LL-37 can be function-dependent. In 2014, we reported successful conversion of LL-37 into17BIPHE2, a stable, selective, and potent antimicrobial, antibiofilm, and anticancer peptide. The European group identified IG-24 derived P60.4 by using the peptide library approach. In 2018, they selected SAAP-148 as a candidate with a reduced binding to blood plasma. Interestingly, both 17BIPHE2 and SAAP-148 eliminated the ESKAPE pathogens and showed topical in vivo antibiofilm efficacy. In addition, a better antibiofilm outcome could be obtained when 17BIPHE2 was used in combination with traditional antibiotics. Finally, I summarize what we have learned from human LL-37 engineering. Video from the Keynote Speaker Dr. Guangshun Wang can be found: https://youtu.be/1OOpTs6Sszk