# Rigidity vs Activity: Design of Gramicidin S Analogs against Multidrug-Resistant Bacteria Based on Molecular Engineering

## TL;DR

This paper explores how the rigidity of antimicrobial peptides affects their effectiveness and safety against drug-resistant bacteria.

## Contribution

The study introduces gramicidin S analogs with varying rigidity to optimize antimicrobial activity and reduce toxicity.

## Key findings

- GSC-FB showed potent activity against Gram-positive bacteria with reduced cytotoxicity.
- GS-L demonstrated broader-spectrum activity, including against Gram-negative strains.
- Flexible or moderately rigid analogs interacted more effectively with membrane models.

## Abstract

Antimicrobial peptides are a promising class of therapeutics
to
address antibiotic resistance; yet, their clinical use is limited
by toxicity and narrow-spectrum activity. To better understand how
conformational rigidity influences efficacy and safety, a series of
β-sheet antimicrobial peptide analogs based on gramicidin S
were designed and synthesized. Two stapled derivatives (GSC-FB and GSC-SS) and a flexible linear analog (GS-L) were
prepared and evaluated. GSC-FB retained potent activity
against Gram-positive bacteria with a significantly reduced cytotoxicity.
GS-L, characterized by increased conformational flexibility, showed
broader-spectrum activity, including activity against Gram-negative
strains, and similarly improved safety. Circular dichroism spectroscopy
revealed that all analogs displayed structural perturbations relative
to native gramicidin S. Molecular dynamics simulations indicated that
only flexible or moderately rigid analogs effectively interact with
membrane models. These findings demonstrate that conformational rigidity
is a key parameter in the design of antimicrobial peptides, enabling
the optimization of antimicrobial potency while mitigating toxicity.