Biomimetic facially amphiphilic antibacterial oligomers with conformationally stiff backbones

Area of Science:

• Medicinal Chemistry
• Biochemistry
• Materials Science

Background:

• Foldamers are emerging as promising therapeutic agents.
• Designing conformationally restricted foldamers with specific functionalities is a key challenge.
• Amphiphilic molecules are known for their antimicrobial properties.

Purpose of the Study:

• To design and synthesize a novel foldamer with a conformationally stiff and facially amphiphilic backbone.
• To evaluate the antimicrobial activity of the designed foldamer.
• To investigate the selectivity of the foldamer towards bacterial cells over human red blood cells.

Main Methods:

• Design guided by Density-Functional Theory (DFT) calculations.
• Synthesis of the foldamer using arylamide bonds around a 4,6-dicarboxy pyrimidine core.
• Conformational analysis using X-ray crystallography and solution Nuclear Magnetic Resonance (NMR) spectroscopy.
• Antimicrobial activity testing against Gram-negative (E. coli) and Gram-positive (B. subtilis) bacteria.

Main Results:

• The designed foldamer exhibits excellent antimicrobial activity with a minimal inhibitory concentration (MIC) of 0.8 microg/ml.
• The foldamer demonstrated 18-fold greater activity against bacterial cells compared to human red blood cells, indicating high selectivity.
• DFT calculations accurately predicted the foldamer's conformation and NMR chemical shifts, validating the design approach.

Conclusions:

• A conformationally stiff, facially amphiphilic foldamer with potent and selective antimicrobial activity has been successfully designed and synthesized.
• The study highlights the potential of rational design, aided by computational methods, in developing new antimicrobial agents.
• This foldamer represents a promising lead compound for further development as an antibacterial therapeutic.