Targeting intracellular of populations Pseudomonas aeruginosa with peptide-mimetic therapies: individual efficacy and synergistic rescue of obsolete antibiotics.

Pseudomonas aeruginosa is a leading cause of human infections, with current treatment options severely limited by high levels of antimicrobial resistance. Historically considered to be an extracellular pathogen, recent evidence has emerged that P. aeruginosa is able to survive and replicate within human cells. These intracellular niches present an additional clinical challenge and may serve as bacterial reservoirs associated with chronic infections that are particularly difficult to eradicate. Here we describe the application of a novel peptide-based therapeutic against recalcitrant populations of bacteria residing within lung epithelial cells. This antimicrobial peptoid is able to target intracellular bacteria without harming host cells. In addition, we have shown that peptoid TM5 exhibits synergy with three antibiotics that otherwise have low efficacy against P. aeruginosa, effectively rescuing drugs that have become clinically obsolete. These synergistic combination therapies are also capable of reducing intracellular bacterial reservoirs, opening the door for potential new strategies against chronic P. aeruginosa infections.