Development of Targeted Antipseudomonal Bactericidal Prodrugs

铜绿假单胞菌引起的血流感染（BSI）病死率高。它们经常出现在 患有肺炎、尿路感染、手术部位感染的患者，或患有重度 基础疾病，包括免疫抑制或化疗诱导的中性粒细胞减少症。系统P。 铜绿假单胞菌由于其强大的宿主积累、高毒力和广泛的耐药性而特别难以治疗。 对常规抗生素的多药耐药性（MDR）。因此，与铜绿假单胞菌的BSI构成显著的 对公众健康的威胁。与传统的抗生素不同，抗菌肽和聚合物（AMP）有助于 通过随机双层破坏的细菌细胞死亡。尽管他们的潜力和承诺，AMP还没有 在临床上获得广泛的成功，主要是由于它们的全身细胞毒性。AMP的少数例子之一 被批准用于临床的是一类称为多粘菌素的抗微生物脂肽。这些化合物是 是治疗MDR铜绿假单胞菌的最后手段，并且主要由于肾毒性问题而限制了它们的使用。到 解决了困扰所有AMP的关键选择性问题，包括我们生产的新合成AMP。 实验室（BDT-4G）对多粘菌素耐药铜绿假单胞菌分离株有效，我们将建立靶向 抗体缀合物（ABC）前药，其主动靶向铜绿假单胞菌并释放活性药物 仅在感染部位分泌的宿主因子存在下才具有抗微生物性。这种作用机制， 与抗体-药物缀合物领域中使用的类似， 暴露，同时保持感染部位的抗微生物效力。靶向铜绿假单胞菌的抗体 （Cam-003）应在全身施用后快速定位于细菌细胞，从而使细胞内的细胞聚集。 在铜绿假单胞菌表面缀合AMP。通过宿主定向的接头裂解从抗体释放AMP 会导致细菌溶解通过宿主因子而不是细菌酶的接头切割将最大限度地减少酶的活性。 病原体通过诱变逃避ABC处理的能力。我们假设， 通过抗体靶向在感染部位的停留时间将提高ABC效力并最小化 对宿主的细胞毒性。开发ABC作为一类新的可消除MDR的抗菌化合物 P.铜绿假单胞菌将具有巨大的益处，特别是对于住院和免疫受损的患者。的 考虑到当前抗生素耐药性加速的时代，这一努力的影响怎么强调都不过分。

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.