UC Irvine

Antibiotic resistance among Gram-negative organisms is a major challenge. Some molecules, including antimicrobial peptides such as polymyxin B (PMB), are antibacterial but toxic due to low specificity, causing poor clinical utility. Drug delivery to bacterial cells using a biocompatible nanomaterial is a possible approach to securing such drugs. We engineered a nonlytic phage to recognize the lipopolysaccharide of Gram-negative bacteria and cross-linked thousands of peptides per virion, making "PMB-M13^αLPS". PMB-M13^αLPS reduced the minimum inhibitory concentration in vitro by ∼2 orders of magnitude across multiple pathogen strains. Immunocompetent mice with multidrug-resistant P. aeruginosa pneumonia or corneal infection were effectively treated by PMB-M13^αLPS, which showed potency ∼2 orders of magnitude greater in vivo compared to that of PMB. PMB-M13^αLPS was well-tolerated, with no toxic effects. Conjugates of antimicrobial peptides and synthetic phages combine engineerable targeting with large payload capacity, improving potency and therapeutic index for otherwise toxic molecules.