Metallohelices that kill Gram-negative pathogens using intracellular antimicrobial peptide pathways.

Area of Science:

• Supramolecular Chemistry
• Antimicrobial Drug Discovery
• Biophysics

Background:

• Natural cationic antimicrobial peptides (CAMPs) are crucial for innate immunity but face development challenges.
• Developing synthetic alternatives with similar efficacy and improved properties is a key goal in antimicrobial research.

Purpose of the Study:

• To synthesize and characterize novel water-compatible metallohelices with CAMP-like architectures.
• To evaluate the antimicrobial activity and mechanisms of action of these metallohelices against pathogenic bacteria.
• To explore the potential of CAMP-inspired scaffolds for developing new antimicrobial agents.

Main Methods:

• Self-assembly of non-peptidic organic components around iron ions to form metallohelices.
• Antimicrobial activity assays against various bacterial strains, including Gram-negative pathogens.
• Cellular uptake studies using E. coli, biophysical measurements, whole genome sequencing, and transcriptomic analysis to elucidate mechanisms.

Main Results:

• Synthesized metallohelices exhibit architecture similar to CAMPs and potent, structure-dependent antibacterial activity.
• A key compound entered E. coli cells without membrane disruption, localizing near cellular poles.
• Mechanisms include G-quadruplex DNA binding, inhibition of DNA gyrase and topoisomerase I, and activation of cellular stress responses.

Conclusions:

• Metallohelices represent a viable synthetic alternative to natural CAMPs for antimicrobial drug discovery.
• The observed multi-target mechanism hinders resistance development, addressing a key challenge in antimicrobial therapy.
• CAMP-inspired chemical scaffolds offer a realistic approach to overcoming practical barriers associated with natural CAMPs.