# Design of Hybrid Bioactive Peptides Derived From Cecropin and Cathepsin for Therapeutic Application

## TL;DR

This paper designs hybrid peptides with antimicrobial properties, showing they can target bacteria like E. coli and are safe in early tests.

## Contribution

The study introduces a novel computational and experimental framework for designing hybrid bioactive peptides with antimicrobial activity.

## Key findings

- Hybrid peptides showed potent inhibition of planktonic cultures and biofilms.
- Peptides exhibited high safety with no toxicity in erythrocyte or larvae models.
- Molecular docking revealed interactions with E. coli enzymes DNA gyrase and thymidylate synthase.

## Abstract

The escalating global health crisis of antimicrobial resistance demands the urgent development of novel therapeutic agents with new mechanisms of action. Bioactive peptides (BAPs), and specifically antimicrobial peptides (AMPs), represent a highly promising class of candidates due to their broad‐spectrum activity and superior biocompatibility compared to conventional antibiotics. This manuscript presents a novel approach to drug discovery by designing multifunctional hybrid peptides through the strategic fusion of conserved domains from cecropin and cathepsin‐derived sequences. We established an integrated in silico pipeline, utilizing machine learning for activity prediction and comprehensive ADMET profiling to rationally select three lead candidates with optimal physicochemical properties. Experimental validation confirmed their potent efficacy in vitro, demonstrating significant inhibition of both planktonic cultures and resilient biofilms. Critically, these peptides displayed a high safety profile, with no toxicity in erythrocyte or Galleria mellonella larvae models. To elucidate their mode of action, target fishing and molecular docking studies were conducted, revealing high‐affinity interactions with essential
E. coli
enzymes, DNA gyrase, and thymidylate synthase. By combining computational design with robust biological validation, this work establishes a streamlined framework for accelerating anti‐infective discovery and positioning these engineered hybrid BAPs as a promising class of antimicrobial agents.

This study designs hybrid bioactive peptides from cecropins and cathepsins, showcasing their antimicrobial potential. Notably, we identify critical interactions with microbial targets, DNA gyrase and thymidylate synthase in
E. coli
, revealing insights into their mechanisms of action as promising novel antimicrobial agents.