Antimicrobial Peptides with High Proteolytic Resistance for Combating Gram-Negative Bacteria

Poor
proteolytic resistance is an urgent problem to be solved in
the clinical application of antimicrobial peptides (AMPs), yet common
solutions, such as complicated chemical modifications and utilization
of d-amino acids, greatly increase the difficulty and cost
of producing AMPs. In this work, a set of novel peptides was synthesized
based on an antitrypsin/antichymotrypsin hydrolytic peptide structure
unit (XYPX)n (X represents I, L, and V;
Y represents R and K), which was designed using a systematic natural
amino acid arrangement. Of these peptides, 16 with seven
repeat units had the highest average selectivity index (GMSI = 99.07) for all of the Gram-negative bacteria tested and remained
highly effective in combating Escherichia coli infection in vivo. Importantly, 16 also had dramatic
resistance to a high concentration of trypsin/chymotrypsin hydrolysis
and exerted bactericidal activity through a membrane-disruptive mechanism.
Overall, these findings provide new approaches for the development
of antiprotease hydrolytic peptides that target Gram-negative bacteria.