Development of Targeted Antipseudomonal Bactericidal Prodrugs

靶向抗假单胞菌杀菌前药的开发

• 批准号: 10678074
• 负责人: Christopher Akinleye Alabi
• 金额: $ 45.53万
• 依托单位: CORNELL UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-02-04 至 2028-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10678074
• 关键词: Acceleration; Address; Anti-Bacterial Agents; Antibiotic Resistance; Antibiotics; Antibodies; Antibody-drug conjugates; Bacteremia; Bacterial Infections; Bacteriolysis; Binding; Biological Availability; Biological Markers; Blood; Blood Circulation; Cell Death; Cell membrane; Cells; Centers for Disease Control and Prevention (U.S.); Chronic lung disease; Clinical; Clinical Research; Development; Dose Limiting; Enzymes; FDA approved; Fatality rate; Fluorescence Resonance Energy Transfer; Frequencies; Genes; Goals; Gram-Negative Bacteria; Hospitalization; Immune; In Vitro; Infection; Injury to Kidney; Integration Host Factors; Intravenous; Kidney; Kinetics; Laboratories; Lead; Libraries; Lipids; Lung infections; Marketing; Matrix Metalloproteinases; Measures; Metabolism; Modeling; Multi-Drug Resistance; Mus; Mutagenesis; Neutropenia; Patient-Focused Outcomes; Patients; Peptides; Pharmaceutical Preparations; Pharmacologic Actions; Pneumonia; Polymers; Polymyxin B; Polymyxin B resistance; Polymyxin Resistance; Polymyxins; Prodrugs; Property; Proteins; Pseudomonas aeruginosa; Pseudomonas aeruginosa infection; Public Health; Research; Resistance; Resistance development; Respiratory Tract Infections; Sepsis; Site; Source; Stream; Surface; Surgical Wound Infection; Therapeutic immunosuppression; Thrombin; Time; Toxic effect; Urinary tract infection; Variant; Virulence; World Health Organization; absorption; antimicrobial; antimicrobial peptide; antimicrobial resistant infection; bacterial resistance; bactericide; cancer therapy; chemotherapy; clinically relevant; combat; comorbidity; cytotoxicity; design; drug clearance; improved; in vivo; mouse model; nephrotoxicity; novel; pathogen; residence; resistant strain; small molecule; success

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.

由铜绿假单胞菌引起的血流感染 (BSI) 死亡率很高，通常发生在。 患有肺炎、尿路感染、手术部位感染或重症患者 潜在疾病，包括免疫抑制或化疗引起的中性粒细胞减少症。 铜绿假单胞菌因其宿主积累旺盛、毒力高、传播范围广而特别难以治疗。 因此，铜绿假单胞菌的 BSI 具有重要意义。 与传统抗生素不同，抗菌肽和聚合物（AMP）有利于消除对公众健康的威胁。 尽管 AMP 具有强大的功效和前景，但它尚未通过随机双层破坏导致细菌细胞死亡。 享有广泛的临床成功，主要是由于它们的全身细胞毒性是 AMP 的少数例子之一。 批准用于临床的是一类称为多粘菌素的抗菌脂肽。 治疗 MDR 铜绿假单胞菌的最后手段，其使用受到限制，主要是由于肾毒性问题。 解决困扰所有 AMP 的关键选择性问题，包括我们生产的新型合成 AMP 实验室（BDT-4G）对多粘菌素耐药铜绿假单胞菌分离株有活性，我们将创建有针对性的 杀菌剂结合物 (ABC) 前药，主动靶向铜绿假单胞菌并释放活性物质 抗菌剂仅在感染部位分泌的宿主因子存在时发挥作用。 与抗体-药物缀合物领域中使用的类似，应减少由于非特异性而引起的毒性 暴露，同时保持感染部位的抗菌效力。 (Cam-003) 在全身给药后应迅速定位于细菌细胞，从而集中 铜绿假单胞菌表面结合的 AMP 通过宿主定向接头裂解从抗体中释放。 将导致宿主因素而不是细菌酶的连接物裂解，从而最大限度地减少细菌溶解。 病原体通过诱变逃避 ABC 处理的能力。 通过抗体靶向在感染部位的停留时间将提高 ABC 效力并最大限度地减少 开发 ABC 作为一类可以根除 MDR 的新型抗菌化合物。 铜绿假单胞菌将带来巨大的益处，特别是对于住院患者和免疫功能低下的患者。 鉴于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。