Structure-Activity Relationship Study of Antimicrobial Peptide with Cross-Kingdom Activity

Area of Science:

• Biochemistry
• Medicinal Chemistry
• Microbiology

Background:

• Antibiotic-resistant pathogens present a critical global health threat, necessitating novel antimicrobial discovery approaches.
• Antimicrobial peptides (AMPs) show promise due to broad-spectrum activity, including against multidrug-resistant strains.
• The SAJO-2 peptide, with a unique d-Phe-2-Abz unit, was previously enhanced via fluorination, increasing potency but also enzymatic susceptibility.

Purpose of the Study:

• To enhance the efficacy and stability of the SAJO-2 antimicrobial peptide.
• To overcome limitations of previous modifications, specifically increased susceptibility to enzymatic digestion.
• To develop novel AMPs with improved resistance to degradation and retained antimicrobial activity.

Main Methods:

• Incorporation of D-amino acids into the peptide backbone.
• Introduction of beta backbone modifications.
• Inclusion of a bulky pentafluorinated amino acid residue.

Main Results:

• All modified SAJO-2 peptides demonstrated resistance to enzymatic degradation by β-trypsin.
• Antimicrobial activity was preserved to varying extents across different microbial organisms.
• The modifications successfully addressed the enzymatic instability issue encountered in prior fluorinated analogs.

Conclusions:

• Engineered SAJO-2 analogs exhibit enhanced stability against enzymatic breakdown.
• These modified AMPs represent a promising avenue for developing new therapeutics against antibiotic-resistant bacteria.
• Further research can optimize these modifications for broad clinical application in combating infectious diseases.