Random Peptide Mixtures as Safe and Effective Antimicrobials against Pseudomonas aeruginosa and MRSA in Mouse Models of Bacteremia and Pneumonia

Antibiotic resistance is a daunting challenge in modern medicine, and novel approaches that minimize the emergence of resistant pathogens are desperately needed. Antimicrobial peptides are newer therapeutics that attempt to do this; however, they fall short because of low to moderate antimicrobial activity, low protease stability, susceptibility to resistance development, and high cost of production. The recently developed random peptide mixtures (RPMs) are promising alternatives. RPMs are synthesized by incorporating a defined proportion of two amino acids at each coupling step rather than just one, making them highly variable but still defined in their overall composition, chain length, and stereochemistry. Because RPMs have extreme diversity, it is unlikely that bacteria would be capable of rapidly evolving resistance. However, their efficacy against pathogens in animal models of human infectious diseases remained uncharacterized. Here, we demonstrated that RPMs have strong safety and pharmacokinetic profiles. RPMs rapidly killed both Pseudomonas aeruginosa and Staphylococcus aureus efficiently and disrupted preformed biofilms by both pathogens. Importantly, RPMs were efficacious against both pathogens in mouse models of bacteremia and acute pneumonia. Our results demonstrate that RPMs are potent broad-spectrum therapeutics against antibiotic-resistant pathogens.