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.

抽象的该项目的目标是优化和研究双靶向尿素缩酚肽的药理学 (UDEP)-利福霉素混合抗生素。这些新药剂在治疗生物膜方面具有令人鼓舞的潜力相关和复杂的革兰氏阳性感染，包括菌血症、假体关节感染和感染性心内膜炎，用标准护理抗生素（如如万古霉素并导致显着的死亡率。大多数抗生素需要活跃的细菌生长才能有效地工作。有些细菌通过缓慢生长或根本不生长来逃避传统抗生素的杀死，即使在高药物浓度下也能长时间存活。这些幸存的细胞导致抗生素耐受性和耐药性，导致反复感染，延长抗生素使用时间治疗，并增加相关的患者护理费用。最近，我们一直在使用基于结构的设计优化 UDEP 抗生素的药理学，克服抗生素耐受性针对非分裂细菌。 UDEP 激活 ClpP 蛋白酶，导致不受控制的蛋白水解，杀死稳定期、休眠、耐抗生素细胞和生物膜。目前利福平与其他抗生素联合用于治疗结核分枝杆菌 (MTB) 和假体关节感染 (PJI)，还通过抑制 DNA 依赖性 RNA 来对抗非分裂细胞聚合酶并在转录过程中阻断 RNA 延伸。除了分享针对生长缓慢的细菌，UDEP 和利福平也有联合使用的要求与其他抗生素一起使用以防止耐药性的产生。我们假设合成一个双靶向 UDEP-利福平混合抗生素将显着减少耐药性的产生并有潜力实现前所未有的针对生物膜和难以治疗的活性感染。单个分子比组合有很多优点，例如，不需要药代动力学相匹配，给药更简单。在这个提案中，我们计划仔细优化 UDEP-利福霉素混合抗生素采用详细的合成和测试级联，以确保药物开发出对体外和体内持久性药物具有有效活性的药物，并且具有安全的药理作用轮廓。将仔细分析新兴先导化合物的作用方式，以研究其目标参与、耐药性发展、对生长和非生长细胞的影响。