Hybrid Antibiotics for Persistent Infections

用于持续感染的混合抗生素

• 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
• 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

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 该项目的目的是优化和研究双靶向尿素depspeptide的药理学 （UDEP） - 实霉素杂交抗生素。这些新代理具有令人鼓舞的潜力来治疗生物膜 - 相关且复杂的革兰氏阴性感染，包括菌血症，假体关节 感染和感染性心内膜炎，很难用标准的护理抗生素治愈 作为万古霉素并引起重大死亡率。大多数抗生素需要主动细菌生长 有效工作。一些细菌通过缓慢或根本不缓慢地生长而逃避传统抗生素的杀戮 允许长时间的药物浓度允许生存。这些幸存的细胞 有助于抗生素耐受性和耐药性，引起复发性感染，延长抗生素 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 设计以优化UDEP抗生素的药理学，从而克服抗生素耐受性 靶向非分裂细菌。 UDEPS激活CLPP蛋白酶，导致不受控制的蛋白水解， 杀死固定相，休眠，耐耐药细胞和生物膜。利福平目前 与其他抗生素结合使用以治疗结核分枝杆菌（MTB）和假体关节 感染（PJI）也通过抑制DNA依赖性RNA具有对非分裂细胞的活性 转录过程中的聚合酶和阻断RNA伸长率。除了分享活动反对 生长缓慢的细菌，UDEPS和利福平也共享了组合使用的要求 使用其他抗生素来防止耐药性发展。我们假设合成双重 靶向UDEP-RIFAMPIN杂交抗生素将导致耐药性的发展明显降低 并有可能实现针对生物膜和难以治疗的前所未有的活动 感染。一个分子比组合具有许多优势，例如，没有必要 要匹配药代动力学和剂量更简单。在此提案中，我们计划仔细优化 UDEP-富霉素杂交抗生素使用详细的合成和测试级联反应，以确保剂是 开发的，在体外和体内具有强大的活动，以及安全的药理 轮廓。新兴线索的行动方式将仔细介绍以研究其目标 参与，耐药性发展，对生长和非生长细胞的影响。