# Bifunctional Peptides Generated by Optimising the Antimicrobial Activity of a Novel Trypsin-Inhibitory Peptide from Odorrana schmackeri

## TL;DR

Scientists designed new bifunctional peptides that can fight drug-resistant bacteria and inhibit trypsin, with promising safety and stability for potential clinical use.

## Contribution

The study introduces novel bifunctional peptides with optimized antimicrobial and trypsin-inhibitory activity derived from a Bowman–Birk-type inhibitor.

## Key findings

- Modified peptides showed potent antimicrobial activity against drug-resistant E. coli strains.
- Peptides exhibited stable membrane interactions and resistance to serum and trypsin.
- Electrostatic interactions were identified as the main force in peptide-membrane binding.

## Abstract

Drug-resistant bacteria cause millions of global infections each year, and the development of alternative antimicrobial drugs has become a serious undertaking. Currently, peptides with antimicrobial activity represent potential candidates for new antibiotic discovery as they are less likely to cause drug resistance in bacteria. In this study, bifunctional peptides with potent trypsin-inhibitory activity and antimicrobial activity were obtained by rational computation-based structural modifications to a novel Bowman–Birk-type inhibitor (BBI) peptide. The analogues not only displayed potent bacterial killing ability against two drug-resistant bacteria strains of E. coli but also an excellent safety profile, as assessed by low haemolytic activity and low anti-proliferation activity on HaCaT cells. Throughout the molecular dynamics simulations, the peptides exhibited stable adsorption onto the mixed POPE/POPG membrane; most amino acid residues of the AMPs remained bound to the membrane surface, with a few amino acid residues partially penetrating the membrane interior. This showed that the electrostatic interactions were the dominant driving force mediating the peptide–membrane associations. In addition, the tested peptides displayed a degree of stability in the presence of salt ions, serum, and trypsin. These modified peptides thus possess potential as clinical antibacterial agents, and the strategies used in structural modification may also provide a different path to developing new antimicrobial peptides.