Development of Targeted Antipseudomonal Bactericidal Prodrugs

由铜绿假单胞菌引起的血液感染(BSI)病死率高。它们经常出现在 肺炎、尿路感染、手术部位感染或重症患者 潜在情况，包括免疫抑制或化疗引起的中性粒细胞减少症。系统性P. 铜绿假单胞菌由于其强大的寄主积累、高毒力和广泛性而特别难以治疗。 对常规抗生素的多重耐药(MDR)。因此，含有铜绿假单胞菌的细菌感染构成了显著的 对公众健康的威胁。与传统抗生素不同，抗菌肽和聚合物(AMP)有助于 细菌细胞通过随机双层破坏而死亡。尽管AMP的效力和前景广阔，但它们还没有 享有广泛的临床成功，主要是由于它们的全身细胞毒性。AMP为数不多的几个例子之一 被批准用于临床的是一类名为多粘菌素的抗菌脂肽。这些化合物是 治疗耐多药铜绿假单胞菌的最后手段，主要是由于肾毒性问题，限制了它们的使用。至 解决困扰所有AMP的关键选择性问题，包括在我们的 实验室(BDT-4G)对多粘菌素耐药铜绿假单胞菌有效，我们将创建有针对性的 抗体结合细菌剂(ABC)前药，主动靶向铜绿假单胞菌并释放活性 只有在宿主因子存在的情况下才能在感染部位分泌抗菌剂。这种作用机制， 与抗体-药物偶联物领域中使用的类似，应该会减少由于非特异性而产生的毒性 暴露，同时保持感染部位的抗菌剂效力。针对铜绿假单胞菌的抗体 (CaM-003)在全身给药时应迅速定位于细菌细胞，从而集中 铜绿假单胞菌表面结合AMP。通过宿主定向的连接子切割从抗体中释放AMP 会导致细菌溶解。由宿主因素而不是细菌酶来裂解连接子将使 病原菌通过诱变逃避ABC处理的能力。我们假设，增加 通过抗体靶向在感染部位的滞留时间将提高ABC的效力并使 对寄主的细胞毒性。开发ABC作为一类可消除MDR的新型抗菌化合物 铜绿假单胞菌将带来巨大的好处，特别是对住院和免疫功能低下的患者。这个 考虑到当前抗生素耐药性加速增长的时代，这一努力的影响怎么强调都不为过。

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.