Fluorinated antimicrobial lysine-based peptidomimetics with activity against methicillin-resistant Staphylococcus...

Area of Science:

• Veterinary Medicine
• Microbiology
• Medicinal Chemistry

Background:

• Staphylococcus pseudintermedius is a common opportunistic pathogen in dogs, causing skin and ear infections.
• The rise of methicillin-resistant S. pseudintermedius (MRSP) presents a significant challenge in companion animal health.
• There is a critical need for new therapeutic agents to combat MRSP infections.

Purpose of the Study:

• To explore structure-activity relationships of peptidomimetics against MRSP.
• To investigate the impact of oligomer length, fluorination, end-group modification, and hydrophobic side chain length on antibacterial activity and hemolytic properties.

Main Methods:

• Synthesis and testing of 37 peptidomimetic compounds.
• Evaluation of antibacterial activity against MRSP and other bacterial strains (S. aureus, E. coli, P. aeruginosa).
• Assessment of hemolytic properties and cell selectivity.

Main Results:

• Fluorination and longer hydrophobic side chains increased compound potency against MRSP without significant increases in hemolysis.
• Reducing peptidomimetic length from 12 to 8 residues maintained antibacterial activity against MRSP.
• End-group modifications enhanced activity against S. aureus, E. coli, and P. aeruginosa but also increased hemolytic properties, lowering cell selectivity.

Conclusions:

• Optimized peptidomimetics, particularly those with fluorination and elongated hydrophobic chains, offer a promising avenue for treating MRSP infections in dogs.
• Peptidomimetic length can be reduced for MRSP targeting, potentially simplifying drug design.
• Further research is needed to balance efficacy and safety, especially concerning end-group modifications and hemolytic effects.