Peptoid polymers for MRSA and other Gram-positive bacteria

DISEASE CATEGORY: Infectious disease

INDICATION: Staphylococcus 
Polymers composed of peptoids, peptide-like molecules whose side chains are attached to the amide nitrogen rather than the alpha carbon and are largely resistant to proteases, could help treat methicillin-resistant Staphylococcus aureus (MRSA) and other Gram-positive infections. Synthesis and screening of peptoid polymers identified a candidate with a minimum inhibitory concentration (MIC) of 12.5 μg/mL against S. aureus that inhibited18 clinically isolated Gram-positive bacterial strains, including several drug resistant strains, with MICs ranging from 1.56 -25 μg/mL. In kinetic culture studies, the polymer caused a 2.7 log reduction in S. aureus in 1 hour, compared with a 0.3 log reduction in 4 hours with a vancomycin control, and killed persister cells generated by high concentration ciprofloxacin treatment. In sequential cultures, S. aureus did not develop resistance to sublethal doses of the polymer. In a mouse mound model of MRSA infection, the polymer decreased bacterial burden in the wound compared with vancomycin. In a keratitis model, the polymer reduced bacterial load, while vancomycin did not. In three lethal peritonitis models, the polymer increased survival compared with vehicle similarly to vancomycin in two cases, and better than vancomycin in one case. Next steps include expanding the structural diversity of peptoid polymers and testing them against a broader range of infections. ...