Targeted Macromolecular Antimicrobial Prodrugs Against Pseudomonas Aeruginosa

世界卫生组织将铜绿假单胞菌列为关键优先1病原体 疾病控制中心将其列为“严重”威胁级别，因为它已成为严重的 对住院和免疫受损患者的威胁。铜绿假单胞菌是感染的常见原因。 包括肺炎、菌血症、尿路感染和手术部位感染。在这方面的抗药性 在过去的十年中，致病微生物显著增长，感染铜绿假单胞菌构成了 对公共卫生和国家安全构成重大威胁。这项拟议的研究旨在开发一类新的 LecB的目标是聚乙二醇化的抗菌素前药，可以安全地清除铜绿假单胞菌引起的感染。这 研究工作直接解决了抗菌聚合物领域取得进展的一个关键障碍- 减轻其非特定行为模式带来的系统毒性，并改善其 生物膜渗透。为了解决困扰所有抗菌聚合物的这一关键的选择性问题， 包括我们生产的新的序列定义的合成抗菌寡硫代乙酰胺(寡硫乙酰胺) 实验室，我们建议合成靶向作用于假单胞菌的大分子前药 铜绿假单胞菌(P.铜绿假单胞菌)，并仅在存在毒力的情况下释放活性抗菌剂寡聚TEA 铜绿假单胞菌排放的因子。这种作用机制类似于抗体-药物领域中使用的机制 结合物，应该减少由于非特异性暴露造成的毒性，同时保持 感染部位的抗菌寡聚TEA。除了将毒性降至最低外，前药上的聚乙二醇会 还有助于生物膜的渗透，从而进一步提高生物膜中寡聚乙酸乙酯的活性。这个 可根除多重耐药铜绿假单胞菌的新型抗菌化合物的开发 将带来巨大的好处，特别是对住院和免疫功能低下的患者。这件事的影响 考虑到当前抗生素耐药性加速增长的时代，努力怎么强调都不为过。

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.