Development of Targeted Antipseudomonal Bactericidal Prodrugs

点击翻译按钮获取中文摘要

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.