Hybrid Antibiotics for Persistent Infections

摘要 本课题的目标是优化和研究双靶向尿素去脂肽的药理作用。 (UDEP)-利福霉素混合抗生素。这些新试剂在治疗生物膜方面具有令人鼓舞的潜力- 伴发和复杂的革兰氏阳性感染，包括菌血症、人工关节 感染和感染性心内膜炎，这些都是很难用标准护理抗生素治愈的，如 和万古霉素一样，会导致大量死亡。大多数抗生素需要活跃的细菌生长才能 高效工作。一些细菌通过生长缓慢或根本不生长来逃避传统抗生素的杀戮， 即使在药物浓度较高的情况下也能长期存活。这些存活的细胞 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，并增加相关的病人护理费用。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，通过以下方式克服抗生素耐药性 以不分裂的细菌为目标。UDEP激活ClpP蛋白水解酶，导致不受控制的蛋白分解， 杀死静止期、休眠的、耐抗生素的细胞和生物膜。利福平，目前 与其他抗生素联合使用治疗结核分枝杆菌(MTB)和人工关节 感染(PJI)，也通过抑制DNA依赖的RNA而对未分裂的细胞具有活性 聚合酶和阻止转录过程中的RNA延长。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，以防止耐药性的发展。我们假设合成一个双重的- 靶向UDEP-利福平杂交抗生素将显著减少耐药性发展 并有可能实现前所未有的对抗生物膜和难治性疾病的活动 感染。单个分子比组合分子有许多优点，例如，没有必要 与药物动力学相匹配，而且给药更简单。在这份提案中，我们计划仔细优化 UDEP-利福霉素混合抗生素使用详细的合成和测试级联以确保试剂 开发出在体外和体内对持久菌具有强大活性的药物，以及一种安全的药理 侧写。将仔细分析新兴线索的行动模式，以研究他们的目标 参与，抗性发展，对生长和非生长细胞的影响。

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.