Sequence Permutation Generates Peptides with Different Antimicrobial and Antibiofilm Activities

Area of Science:

• Microbiology
• Biochemistry
• Drug Discovery

Background:

• Antibiotic resistance is a growing global health threat, projected to cause 10 million deaths annually by 2050.
• Developing novel antimicrobial agents is crucial to combat resistant bacterial infections.

Purpose of the Study:

• To explore sequence permutation as a strategy for generating antimicrobial peptides with distinct activity spectra.
• To identify and characterize novel peptide variants effective against specific pathogens, including methicillin-resistant Staphylococcus aureus (MRSA).

Main Methods:

• Utilized the Antimicrobial Peptide Database (APD) to identify a template peptide.
• Generated a series of eight peptide variants (WW291-WW298) through sequence permutation.
• Assessed antibacterial activity, membrane permeation, cytotoxicity, biofilm disruption, and in vivo efficacy in Galleria mellonella.

Main Results:

• Peptide WW298 demonstrated high activity against Staphylococcus aureus USA300 LAC, including MRSA, and effectively permeated its membranes.
• Peptide WW295 showed inhibitory effects against Escherichia coli and permeated its membranes.
• WW298 disrupted MRSA biofilms more effectively than daptomycin and protected wax moths from MRSA infection.

Conclusions:

• Sequence permutation is a viable strategy for developing antimicrobial peptides with tailored activity spectra.
• This approach, combined with amino acid modulation, can yield narrow-spectrum peptides for targeted pathogen elimination while preserving beneficial microbiota.