Antimicrobial Peptide-Peptoid Hybrids with and without Membrane Disruption

Area of Science:

• Biochemistry
• Medicinal Chemistry
• Microbiology

Background:

• Antimicrobial resistance (AMR) is a growing global health threat.
• Synthetic analogues of antimicrobial peptides (AMPs), such as peptoids, are being explored as novel therapeutics.
• Peptoids can act via membrane disruption or intracellular targeting.

Purpose of the Study:

• To investigate the effect of incorporating peptoid units into a membrane-disruptive AMP.
• To explore the potential transition from membrane disruption to intracellular targeting mechanisms.
• To develop novel antimicrobial agents with improved safety profiles.

Main Methods:

• Gradual introduction of peptoid units into the undecapeptide KKLLKLLKLLL.
• Assessment of α-helical folding, membrane disruption, and antimicrobial activity.
• Evaluation of hemolysis and cytotoxicity.
• Testing activity against Gram-negative bacteria, including multidrug-resistant strains.

Main Results:

• Hybrid peptoids with up to five units retained AMP-like properties (folding, membrane disruption, antimicrobial effects) against resistant bacteria.
• These hybrids showed reduced hemolysis and cytotoxicity.
• Peptoids with three or more units, and the full peptoid, lost membrane-disruptive activity but exhibited potent antibacterial effects in dilute media, suggesting intracellular targeting.
• This behavior mimics proline-rich antimicrobial peptides (PrAMPs).

Conclusions:

• Incorporating peptoid units into AMPs can modulate their mechanism of action.
• Selected peptoid hybrids offer a dual approach: membrane disruption or intracellular targeting.
• These findings highlight peptoids as versatile scaffolds for developing new antibiotics against resistant pathogens.