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Updated: Jul 10, 2025
Antimicrobial Peptides Produced by Selective Pressure Incorporation of Non-canonical Amino Acids
Published on: May 4, 2018
A rationally engineered small antimicrobial peptide with potent antibacterial activity
Lalita Mohan Behera1, Manaswini Ghosh1, Pulkit Kr Gupta1
1Chemical Biology Laboratory, School of Basic Sciences, Indian Institute of Technology Bhubaneswar, Odisha, India.
Abstract:
Antimicrobial resistance (AMR) is a silent pandemic declared by the WHO that requires urgent attention in the post-COVID world. AMR is a critical public health concern worldwide, potentially affecting people at different stages of life, including the veterinary and agriculture industries. Notably, very few new-age antimicrobial agents are in the current developmental pipeline. Thus, the design, discovery, and development of new antimicrobial agents are required to address the menace of AMR. Antimicrobial peptides (AMPs) are an important class of antimicrobial agents for combating AMR due to their broad-spectrum activity and ability to evade AMR through a multimodal mechanism of action. However, molecular size, aggregability, proteolytic degradation, cytotoxicity, and hemolysis activity significantly limit the clinical application of natural AMPs. The de novo design and engineering of a short synthetic amphipathic AMP (≤16 aa, Mol. Wt. ≤ 2 kDa) with an unusual architecture comprised of coded and noncoded amino acids (NCAAs) is presented here, which demonstrates potent antibacterial activity against a few selected bacterial strains mentioned in the WHO priority list. The designer AMP is conformationally ordered in solution and effectively permeabilizes the outer and inner membranes, leading to bacterial growth inhibition and death. Additionally, the peptide is resistant to proteolysis and has negligible cytotoxicity and hemolysis activity up to 150 μM toward cultured human cell lines and erythrocytes. The designer AMP is unique and appears to be a potent therapeutic candidate, which can be subsequently subjected to preclinical studies to explicitly understand and address the menace of AMR.
Insights
A novel synthetic antimicrobial peptide (AMP) was designed to combat antimicrobial resistance (AMR). This peptide shows potent antibacterial activity and is safe for therapeutic use, offering a promising solution to the AMR crisis.
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.
