# Optimized Zebrafish AP2M1A-Derived Decapeptide AP10RW with Robust Stability Suppresses Multidrug-Resistant Bacteria

## TL;DR

Scientists optimized a peptide called AP10RW to create a stable and effective treatment against drug-resistant bacteria.

## Contribution

The paper introduces AP10RW, a redesigned antimicrobial peptide with enhanced stability and broad-spectrum efficacy against multidrug-resistant bacteria.

## Key findings

- AP10RW shows broad-spectrum activity against drug-sensitive and multidrug-resistant bacterial pathogens.
- AP10RW is stable under various environmental stresses like serum exposure, pH changes, and high salt concentrations.
- AP10RW is safe for mammalian cells with low hemolysis and cytotoxicity.

## Abstract

The increasing crisis of antimicrobial resistance requires innovative therapeutic strategies that can overcome the limitations of conventional antibiotics. Based on our previous finding that AP10 (a derivative of AP29) possesses antimicrobial activity but lacks thermal stability, we rationally redesigned ten new AP10 analogues to enhance functional robustness while maintaining efficacy. Among these, AP10RW is identified as the optimal candidate due to its exceptional broad-spectrum activity against both drug-sensitive and multidrug-resistant (MDR) bacterial pathogens. Structural analysis reveals that AP10RW adopts an environmentally responsive conformation, transitioning from random coil to amphiphilic α-helix in membrane-mimicking environments, while demonstrating remarkable stability under challenges including serum exposure, varying pH, high salt concentrations, and thermal stress. Mechanistic studies indicate that AP10RW exerts its effects through multiple bactericidal mechanisms involving initial high-affinity binding to bacterial characteristic molecules (LTA, LPS and PGN), followed by rapid membrane depolarization, ultrastructural damage and the induction of lethal oxidative stress. Notably, this potent antimicrobial efficacy is coupled with exceptional biosafety, demonstrating little hemolysis and negligible cytotoxicity against mammalian cells. This systematic optimization represents a significant advancement in antimicrobial peptide engineering. We have successfully transformed a thermally unstable peptide into a robust therapeutic candidate and positioned AP10RW as a promising clinical candidate for addressing the growing threat of multidrug-resistant infections.