# Role of Structural Modifications in Peptidomimetic Compounds as Potential Antimicrobial Agents against Staphylococcus aureus and Streptococcus pyogenes: Balancing Bioavailability, Safety, and Antimicrobial Activity

## TL;DR

This study explores new peptidomimetic compounds that show promise as topical antimicrobial agents against drug-resistant Gram-positive bacteria like Staphylococcus aureus and Streptococcus pyogenes.

## Contribution

The paper introduces 21 novel peptidomimetic analogues optimized for antimicrobial activity, safety, and bioavailability against Gram-positive pathogens.

## Key findings

- Analogues A-192 and A-164 showed the strongest antimicrobial effects against S. aureus and S. pyogenes.
- Most compounds were inactive against Gram-negative bacteria and showed low to moderate toxicity.
- Computational ADMET modeling suggested these compounds are suitable for topical applications.

## Abstract

The emergence of drug-resistant Gram-positive pathogens,
particularlyStaphylococcus aureusandStreptococcus
pyogenes, has driven the need for novel antimicrobial
agents. This study explores 21 newly synthesized peptidomimetic analogues
of cystatin C N-terminal fragment, designed to enhance
bioactivity, solubility, and safety. These compounds were evaluated
for antimicrobial potency, cytotoxicity, pro-proliferative effects,
and pharmacokinetic properties. Key findings indicate that analogues
A-192 and A-164 exhibited the strongest antimicrobial effects against S. aureus and S. pyogenes. Most compounds were inactive against Gram-negative bacteria. Cytotoxicity
profiling identified several derivatives with low to moderate toxicity
and favorable pro-proliferative effects at specific concentrations.
Stability tests confirmed the robustness in aqueous and plasma environments.
Computational absorption, distribution, metabolism, excretion, and
toxicity (ADMET) modeling revealed low gastrointestinal absorption,
but favorable parameters for topical applications. Exploratory analyses
(principal component analysis (PCA) and two-way hierarchical cluster
analysis (2D-HCA)) linked structural featuressuch as branching,
molecular weight, and solubility, with biological activity. These
results support the potential of structurally optimized peptidomimetics
as targeted, topical therapeutics for Gram-positive infections and
provide a rationale for further preclinical development.