Bloodstream infections (BSI) caused by Pseudomonas aeruginosa have a high fatality rate. They often arise in
patients suffering from pneumonia, urinary tract infections, surgical site infections, or patients with severe
underlying conditions, including immunosuppression or chemotherapy-induced neutropenia. Systemic P.
aeruginosa is particularly difficult to treat due to its robust host accumulation, high virulence, and extensive
multidrug resistance (MDR) to conventional antibiotics. As such, BSIs with P. aeruginosa pose a significant
threat to public health. Unlike traditional antibiotics, antimicrobial peptides and polymers (AMPs) facilitate
bacterial cell death via stochastic bilayer disruption. Despite their potency and promise, AMPs have yet to
enjoy broad clinical success, primarily due to their systemic cytotoxicity. One of the few examples of AMPs
approved for clinical use is a class of antimicrobial lipopeptides called polymyxins. These compounds are the
last resort to treat MDR P. aeruginosa and are limited in their use primarily due to nephrotoxicity concerns. To
address the critical selectivity problem that plagues all AMPs, including new synthetic AMPs made in our
laboratory (BDT-4G) that are active on polymyxin resistant P. aeruginosa isolates, we will create targeted
antibody bactericide conjugate (ABC) prodrugs that actively target P. aeruginosa and release the active
antimicrobial only in the presence of host factors secreted at the infection site. 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 antimicrobial potency at the infection site. The antibody targeting P. aeruginosa
(Cam-003) should rapidly localize to the bacterial cells upon systemic administration, thus concentrating the
conjugated AMP at the P. aeruginosa surface. AMP release from the antibody via host-directed linker cleavage
will lead to bacteriolysis. Linker cleavage by host factors instead of bacterial enzymes will minimize the
pathogen’s capacity to escape the ABC treatment via mutagenesis. We hypothesize that increasing the
residence time at the infection site through antibody targeting will improve ABC potency and minimize
cytotoxicity to the host. Developing ABCs as a new class of antibacterial compounds that can eradicate MDR
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.