Complexation-Aided Selectivity Amplification: A Strategy to Mitigate Peptidomimetics' Toxicity Issues in...

Area of Science:

• Biochemistry
• Materials Science
• Microbiology

Background:

• Antimicrobial peptidomimetics (AMPMs) offer resistance-resistant antibacterial properties but lack selectivity, limiting their therapeutic use.
• Poor selectivity against eukaryotic cells results in low therapeutic indices and incompatibility with current treatment strategies.

Purpose of the Study:

• To develop a strategy for enhancing the selectivity of AMPMs towards bacterial cells.
• To create safer and more effective antimicrobial agents by improving AMPM therapeutic indices.

Main Methods:

• Complexation-aided selectivity amplification strategy using anionic polyelectrolytes and AMPMs.
• Formation of kinetically and thermodynamically stable AMPM-polyelectrolyte complexes.
• Evaluation of complexed AMPM selectivity for prokaryotic versus eukaryotic cell membranes.

Main Results:

• Enhanced AMPM selectivity for negatively charged bacterial membranes over eukaryotic membranes.
• Demonstrated low toxicity of AMPM-polyelectrolyte complexes in cell and animal models.
• Retained AMPM advantages: resistance-resistance, broad-spectrum activity, and rapid killing.

Conclusions:

• Complexation-aided selectivity amplification is a viable strategy to improve AMPM safety and efficacy.
• The developed AMPM-polyelectrolyte complexes offer a low-toxicity alternative for antimicrobial therapy.
• This approach broadens the applicability of AMPMs and facilitates combination with existing antibiotics.