Antimicrobial Random Peptide Mixtures Eradicate Acinetobacter baumannii Biofilms and Inhibit Mouse Models of Infection

Antibiotic resistance is one of the greatest crises in human medicine. Increased incidents of antibiotic resistance are linked to clinical overuse and overreliance on antibiotics. Among the ESKAPE pathogens, Acinetobacter baumannii, especially carbapenem-resistant isolates, has emerged as a significant threat in the context of blood, urinary tract, lung, and wound infections. Therefore, new approaches that limit the emergence of antibiotic resistant A. baumannii are urgently needed. Recently, we have shown that random peptide mixtures (RPMs) are an attractive alternative class of drugs to antibiotics with strong safety and pharmacokinetic profiles. RPMs are antimicrobial peptide mixtures produced by incorporating two amino acids at each coupling step, rendering them extremely diverse but still defined in their overall composition, chain length, and stereochemistry. The extreme diversity of RPMs may prevent bacteria from evolving resistance rapidly. Here, we demonstrated that RPMs rapidly and efficiently kill different strains of A. baumannii, inhibit biofilm formation, and disrupt mature biofilms. Importantly, RPMs attenuated bacterial burden in mouse models of acute pneumonia and soft tissue infection and significantly reduced mouse mortality during sepsis. Collectively, our results demonstrate RPMs have the potential to be used as powerful therapeutics against antibiotic-resistant A. baumannii.