An unprecedented public health threat, antibiotic resistance is especially pronounced due to a paucity of antibiotics available to treat resistant bacteria. In particular, nosocomial Pseudomonas aeruginosa infections are notoriously difficult to treat due to biofilm formation and intracellular survival through the evasion of innate immunity thus preventing antibiotic accessibility and contributing to chronic infections in patients. Hence, it is imperative to find novel treatments against resistant bacteria to reduce patient morbidity and mortality. We have recently developed well-defined biodegradable guanidinium-functionalized polycarbonates as effective antimicrobial agents through organocatalytic living ring-opening polymerization (OROP). This controlled polymerization method allowed for the incorporation of monomers with diverse functionalities, thereby enabling numerous antimicrobial macromolecules to be designed. These polymers are bactericidal against P. aeruginosa by unique mechanism - membrane translocation followed by binding of proteins and genes. With multiple targets, these polymers are transparent to resistance development. To prevent serum inactivation, improve bioavailability and improve biocompatibility, acid-functionalized polycarbonate/PEG block co-polymers were synthesized to encapsulate the cationic polymers into nanocomplexes through coacervation. These nanocomplexes demonstrated stable kinetics and minimal aggregation in serum-containing medium. Furthermore, the nanocomplexes were also neutral and highly modular with tunable particle size. While the nanocomplexes had comparatively higher minimal inhibitory concentrations (MICs) than their respective cationic antimicrobial polymers, they had minimal cytotoxicity in mammalian cells. The nanocomplexes were highly selective and bactericidal against both extra- and intracellular bacteria with negligible in vitro and in vivo toxicity. Following several doses of the nanocomplexes, complete eradication of intracellular P. aeruginosa was achieved, demonstrating the use of nanocomplexes for targeted killing of intracellular bacteria, thereby serving as a potential viable alternative to failing antibiotics in the clinic.

Delivery of antimicrobial polymers through coacervation to mitigate toxicity

2019 Spring National Meeting

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