Helicity Modulation Improves the Selectivity of Antimicrobial Peptoids
Ho Yeon Nam, Jieun Choi, S Dinesh Kumar1
1Department of Biomedical Science, Graduate School, and Department of Cellular and Molecular Medicine, School of Medicine, Chosun University, Gwangju 61452, Republic of Korea.
ACS Infectious Diseases
|September 1, 2020
Summary
Modulating antimicrobial peptide (AMP) helicity enhances bacterial pathogen targeting. A new peptoid, 17, shows potent broad-spectrum activity and superior selectivity by disrupting bacterial membranes while sparing host cells.
Area of Science:
- Biochemistry
- Medicinal Chemistry
- Microbiology
Background:
- Antimicrobial peptides (AMPs) are crucial in innate immunity but often face challenges with toxicity and resistance.
- Modulating conformational flexibility, specifically helicity, is a promising strategy to enhance AMP efficacy and selectivity.
- Developing novel antimicrobial agents is critical due to the rise of multi-drug-resistant pathogens.
Purpose of the Study:
- To investigate the impact of helicity modulation on antimicrobial peptoids' activity and selectivity.
- To synthesize and characterize a library of helicity-modulated antimicrobial peptoids.
- To identify specific peptoid structures with improved efficacy against bacterial pathogens and reduced host cell toxicity.
Main Methods:
- Synthesis of a library of position-specific, helix-inducing antimicrobial peptoids.
- Assessment of antimicrobial activity and selectivity against bacterial pathogens and human erythrocytes.
- Dye-uptake assays and high-resolution imaging to elucidate the mechanism of action.
- Comparison of metabolic stability with existing AMPs like pexiganan.
Main Results:
- Peptoid 17, a moderately helical variant, exhibited a >20-fold increase in selectivity compared to a fully helical peptoid (Peptoid 1).
- Peptoid 17 demonstrated potent, broad-spectrum antimicrobial activity, including against multi-drug-resistant strains.
- Peptoid 17 displayed superior metabolic stability over pexiganan, suggesting potential for lower dosage and reduced toxicity.
- Mechanism of action involves membrane disruption, with high selectivity attributed to differential interactions with bacterial versus erythrocyte membranes.
Conclusions:
- Helicity modulation is an effective strategy for designing highly selective antimicrobial peptoids.
- Peptoid 17 represents a promising lead compound for developing new antibiotics against resistant bacteria.
- Differential membrane interaction based on conformational characteristics offers a novel approach to enhance antimicrobial selectivity.
