Targeted Macromolecular Antimicrobial Prodrugs Against Pseudomonas Aeruginosa

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The World Health Organization lists Pseudomonas aeruginosa (P. aeruginosa) as a critical priority 1 pathogen and the Center for Disease Control has it listed at a threat level of “serious” because it has become a severe threat for hospitalized and immune-compromised patients. P. aeruginosa is a common cause of infections including pneumonia, bacteremia, urinary tract infections, and surgical site infections. Drug resistance in this pathogenic organism has grown significantly in the last decade and infections with P. aeruginosa pose a significant threat to public health and national security. The proposed research seeks to develop a new class of LecB targeted PEGylated antimicrobial prodrugs that can safely clear infections caused by P. aeruginosa. This research effort directly addresses a critical barrier to progress in the field of antimicrobial polymers – mitigating their systemic toxicity brought about by their non-specific mode of action and improving their biofilm penetration. To address this critical selectivity problem that plagues all antimicrobial polymers, including new sequence-defined synthetic antimicrobial oligothioetheramides (oligoTEAs) made in our laboratory, we propose the synthesis of targeted macromolecular prodrugs that actively target Pseudomonas aeruginosa (P. aeruginosa) and release the active antimicrobial oligoTEA only in the presence of virulence factors emitted by P. aeruginosa. This mechanism of action, similar to that used in the field of antibody-drug conjugates, should decrease toxicity due to non-specific exposure while maintaining the potency of the antimicrobial oligoTEA at the site of infection. In addition to minimizing toxicity, the PEG on the prodrug will also facilitate biofilm penetration thus further improving activity of the oligoTEAs in a biofilm. The development of new classes of antibacterial compounds that can eradicate multi-drug resistant P. aeruginosa will be of immense benefit, particularly for hospitalized and immune-compromised patients. The impact of this effort cannot be overstated given the current era of accelerated antibiotic resistance.