# Targeted Modification of the Antimicrobial Peptide DGL13K Reveals a Naturally Optimized Sequence for Topical Applications

## TL;DR

Researchers found that the antimicrobial peptide DGL13K is already highly optimized for topical use due to its stability, broad effectiveness, and low toxicity.

## Contribution

The study demonstrates that DGL13K's natural sequence is already optimized, with targeted modifications failing to improve its therapeutic properties significantly.

## Key findings

- Modifications to DGL13K did not significantly improve its antimicrobial potency or reduce toxicity compared to the original sequence.
- DGL13K and its variants showed reduced antibacterial efficacy in the presence of 50% serum, limiting systemic applications.
- DGL13K is a promising candidate for topical treatments due to its stability, broad-spectrum activity, and low resistance profile.

## Abstract

Antimicrobial peptides are potential alternatives to conventional antibiotics, primarily due to broad-spectrum activity and low propensity for inducing bacterial resistance. However, their clinical translation faces challenges, including peptide stability and potential mammalian cell toxicity. This study centers on DGL13K, an all D-amino acid peptide, which overcomes proteolytic susceptibility and demonstrates notable stability and broad-spectrum bactericidal activity without inducing de novo bacterial resistance. This work aimed to enhance the therapeutic properties of DGL13K by using targeted modifications to increase antimicrobial potency and decrease toxicity, as determined by hemolysis. DGL13K derivatives were synthesized and tested, involving amino acid substitutions, stereochemical alterations, and N-terminal functionalization with polyethylene glycol (PEG) or myristoylate. While some modifications altered bacterial specificity and reduced hemolytic activity, none of the tested alterations resulted in a substantial overall improvement compared to the parent DGL13K sequence. Furthermore, the antibacterial efficacy of DGL13K and its variants was significantly inhibited in the presence of 50% serum, suggesting limitations for systemic applications. The findings suggest that the DGL13K sequence, derived from an evolutionarily selected protein, is already highly optimized. Given its stability, broad-spectrum efficacy, in vivo activity, low resistance profile, and high safety margin, DGL13K is a promising therapeutic candidate for topical/localized infections.