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Hybrid Antibiotics for Persistent Infections

用于持续感染的混合抗生素

基本信息

批准号：
10780719
负责人：
Michael LaFleur
金额：
$ 86.09万
依托单位：
ST. JUDE CHILDREN'S RESEARCH HOSPITAL
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：
2023-09-26 至 2028-07-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10780719
关键词：
Affect Antibiotic Resistance Antibiotic Therapy Antibiotics Bacteremia Bacteria Binding Proteins Biochemical Biological Assay Cell Survival Cells DNA-Directed RNA Polymerase Data Depsipeptides Diabetic Foot Ulcer Dose Drug Kinetics Ensure Foreign Bodies Gene Expression Profiling Genetic Transcription Genus Hippocampus Goals Growth Histopathology Hybrids In Vitro Individual Indwelling Catheter Infection Infective endocarditis Interphase Cell Lead Lesion Measures Microbial Biofilms Microsomes Mitochondria Modeling Modification Monitor Morbidity - disease rate Multi-Drug Resistance Mus Mycobacterium tuberculosis New Agents Patient Care Peptide Hydrolases Periprosthetic joint infection Pharmaceutical Preparations Pharmacology Pharmacology Study Phase Plasma Plasma Proteins Population Proteolysis Proteomics RNA RNA Polymerase Inhibitor RNA Synthesis Inhibition Resistance Resistance development Rifabutin Rifampicin resistance Rifampin Rifamycins Safety Septicemia Solubility Staphylococcus aureus Structure Structure-Activity Relationship System Testing Thigh structure Urea Vancomycin Work acute infection analog antibiotic tolerance antimicrobial care costs chronic infection cytotoxicity density design efficacy evaluation efficacy study improved in vitro Assay in vivo in vivo Model in vivo evaluation knowledge base methicillin resistant Staphylococcus aureus mortality mouse model novel pathogen persistent bacteria pharmacologic pre-clinical prevent recurrent infection resistance frequency resistant strain screening single molecule standard of care subcutaneous

项目摘要

Abstract The goal of this project is to optimize and study the pharmacology of dual-targeting urea depsipeptide (UDEP)-rifamycin hybrid antibiotics. These new agents have encouraging potential to treat biofilm- associated and complicated Gram-positive infections including bacteremia, prosthetic joint infections, and infective endocarditis, which are difficult to cure with standard of care antibiotics such as vancomycin and cause significant mortality. Most antibiotics require active bacterial growth to work effectively. Some bacteria evade killing by traditional antibiotics by growing slowly or not at all, allowing for survival even at high drug concentrations for prolonged periods. These surviving cells contribute to antibiotic tolerance and resistance, cause recurrent infections, prolong antibiotic therapy, and increase associated patient care costs. Recently, we have been using structure-based design to optimize the pharmacology of UDEP antibiotics, which overcome antibiotic tolerance by target non-dividing bacteria. UDEPs activate the ClpP protease causing uncontrolled proteolysis, killing stationary phase, dormant, antibiotic-tolerant cells, and biofilms. Rifampin, currently prescribed in combination with other antibiotics to treat M. tuberculosis (MTB) and prosthetic joint infections (PJI), also has activity against non-dividing cells by inhibiting DNA-dependent RNA polymerase and blocking RNA elongation during transcription. In addition to sharing activity against slowly-growing bacteria, UDEPs and rifampin also share the requirement to be used in combination with other antibiotics to prevent resistance development. We hypothesized that synthesizing a dual- targeting UDEP-rifampin hybrid antibiotic would result in significantly less resistance development and have the potential to achieve unprecedented activity against biofilms and difficult-to-treat infections. A single molecule has many advantages over a combination, for example, there is no need to match the pharmacokinetics, and dosing is simpler. In this proposal, we plan to carefully optimize UDEP-Rifamycin hybrid antibiotics using a detailed synthesis and testing cascade to ensure agents are developed that have potent activity against persisters in vitro and in vivo, and a safe pharmacological profile. The mode of action of the emerging leads will be carefully profiled to study their target engagement, resistance development, effects on growing and non-growing cells.

摘要