Cyclic dipeptide-based antimicrobials with potent antibacterial activity

Area of Science:

• Medicinal Chemistry
• Microbiology
• Drug Discovery

Background:

• Antibiotic resistance poses a significant global health threat.
• Peptide-based antibacterial agents offer a promising strategy due to their membrane-targeting mechanisms and potential for reduced resistance.
• Developing novel antibacterial agents with low resistance is an urgent priority.

Purpose of the Study:

• To design and synthesize novel quaternary ammonium-modified cyclic dipeptides.
• To evaluate the antibacterial activity, cytotoxicity, and resistance potential of these compounds.
• To investigate the mechanism of action and efficacy in preclinical infection models.

Main Methods:

• Synthesis of quaternary ammonium-modified cyclic dipeptides via quaternization reaction.
• Systematic investigation of antibacterial activity (MIC values) against *S. aureus* and *E. coli*.
• Cytotoxicity assays, mechanism of action studies (membrane disruption), biofilm inhibition assays, and *in vivo* efficacy studies in mouse infection models.

Main Results:

• The optimal compound, cHH8-6, exhibited potent antibacterial activity with MIC values of 2.0 μg mL⁻¹ against *S. aureus* and 3.9 μg mL⁻¹ against *E. coli*.
• cHH8-6 demonstrated membrane-disrupting activity via electrostatic interactions with bacterial membranes.
• The compound effectively inhibited and eradicated bacterial biofilms and showed significant efficacy in reducing bacterial load in mouse models with negligible toxicity.

Conclusions:

• Quaternary ammonium-modified cyclic dipeptides represent a promising class of novel antibacterial agents.
• cHH8-6 displays potent broad-spectrum antibacterial activity, low toxicity, and a reduced likelihood of inducing resistance.
• This study offers a novel therapeutic approach for combating bacterial infections and addressing the challenge of antibiotic resistance.