A rationally engineered small antimicrobial peptide with potent antibacterial activity

Area of Science:

• Biochemistry and Medicinal Chemistry
• Drug Discovery and Development
• Microbiology and Infectious Diseases

Background:

• Antimicrobial resistance (AMR) is a global health crisis, exacerbated by a lack of new antimicrobial agents in development.
• Antimicrobial peptides (AMPs) offer broad-spectrum activity and novel mechanisms to overcome AMR, but natural AMPs face limitations like degradation and toxicity.
• Addressing the AMR pandemic necessitates the design and development of innovative antimicrobial therapeutics.

Purpose of the Study:

• To design and engineer a novel, short synthetic antimicrobial peptide (AMP) with enhanced therapeutic properties.
• To evaluate the antibacterial efficacy and safety profile of the designed AMP against priority bacterial pathogens.
• To explore the potential of synthetic AMPs as a viable strategy against the growing threat of antimicrobial resistance.

Main Methods:

• De novo design and synthesis of a short amphipathic AMP (≤16 amino acids, ≤2 kDa) incorporating coded and non-coded amino acids.
• Assessment of antibacterial activity against WHO priority list bacterial strains.
• Evaluation of membrane permeabilization, proteolytic stability, cytotoxicity, and hemolysis activity of the designed peptide.

Main Results:

• The synthetic AMP demonstrated potent antibacterial activity against selected bacterial strains.
• The peptide effectively permeabilized bacterial membranes, leading to growth inhibition and cell death.
• The designed AMP exhibited resistance to proteolysis with negligible cytotoxicity and hemolysis at therapeutic concentrations.

Conclusions:

• A unique synthetic AMP with an unusual architecture was successfully designed and engineered.
• This designer AMP shows significant therapeutic potential as a candidate for combating antimicrobial resistance.
• Further preclinical studies are warranted to validate its efficacy and safety for addressing the AMR menace.