Development of a Selective and Stable Antimicrobial Peptide

Area of Science:

• Biochemistry
• Molecular Biology
• Drug Discovery

Background:

• Antimicrobial peptides (AMPs) show promise as antibiotics due to broad-spectrum activity and low resistance.
• Challenges include loss of activity in physiological conditions and mammalian cell toxicity.
• Developing effective AMPs requires overcoming these limitations for therapeutic translation.

Purpose of the Study:

• To develop a novel synthetic antimicrobial peptide (AMP) with enhanced therapeutic potential.
• To investigate the efficacy and safety of the developed AMP, DTr18-dab.
• To establish design principles for robust AMP development.

Main Methods:

• Rational design and modification of a lead AMP sequence, including incorporation of noncanonical amino acids.
• Evaluation of antibacterial activity against planktonic bacteria and biofilms.
• Assessment of hemolytic activity and efficacy in human serum and a *Galleria mellonella* infection model.

Main Results:

• The evolved AMP, DTr18-dab, exhibits broad-spectrum antibacterial activity and is nonhemolytic.
• DTr18-dab is effective against planktonic bacteria and biofilms, including colistin-resistant strains.
• The peptide demonstrates activity in human serum and a *Galleria mellonella* model, indicating in vivo potential.

Conclusions:

• Synthetic AMPs can be engineered to overcome limitations like physiological instability and toxicity.
• DTr18-dab represents a robust candidate for therapeutic development against bacterial infections.
• Strategic modifications, including noncanonical amino acids, can enhance AMP properties, though their impact can be condition-dependent.