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Development of Targeted Antipseudomonal Bactericidal Prodrugs

靶向抗假单胞菌杀菌前药的开发

基本信息

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
项目类别：
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

项目摘要

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.

铜绿假单胞菌引起的血液感染（BSI）死亡率高。它们经常出现在