Novel synthetic polymyxins kill Gram-positive bacteria

Area of Science:

• Medicinal Chemistry
• Antimicrobial Research
• Infectious Diseases

Background:

• Staphylococcus aureus, including methicillin-resistant strains (MRSA), is a significant cause of hospital-acquired infections.
• MRSA infections are a growing global health concern, leading to substantial morbidity and mortality.
• MRSA is a primary pathogen in cystic fibrosis lung infections.

Purpose of the Study:

• To develop novel colistin (polymyxin E)-inspired molecules.
• To evaluate the antimicrobial efficacy and toxicity of these new compounds against S. aureus isolates.

Main Methods:

• Synthesis of two novel polymyxin-scaffold molecules.
• Antimicrobial activity testing including time-kill curves and growth curves.
• Biofilm eradication assays, toxicity assessments, and isothermal titration calorimetry.

Main Results:

• Both synthesized peptides demonstrated high antimicrobial activity with a Minimum Inhibitory Concentration (MIC) of 4 mg/L.
• The molecules exhibited low relative toxicity, with a selectivity index approaching 23.
• Effective activity was observed against both MRSA and vancomycin-resistant S. aureus (VRSA) isolates.

Conclusions:

• Novel polymyxin-scaffold molecules have been successfully synthesized.
• These compounds are active against challenging S. aureus strains, including MRSA and VRSA.
• This research opens new therapeutic strategies for treating complex S. aureus infections.