Nature inspired treatments for persistent C. difficile infections

针对持续性艰难梭菌感染的自然疗法

• 批准号: 8496728
• 负责人: Julian G Hurdle
• 金额: $ 37.68万
• 依托单位: UNIVERSITY OF TEXAS ARLINGTON
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-08-01 至 2016-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8496728
• 关键词: Acids; Address; Adopted; Affinity; Anti-Bacterial Agents; Antibiotics; Bacteria; Calcium; Cell Death; Cells; Centers for Disease Control and Prevention (U.S.); Chemicals; Clinical; Clostridium difficile; Complex; Data; Development; Drug Kinetics; Evolution; Exhibits; Future; Future Generations; Goals; Gram-Negative Bacteria; Healthcare; Hospitals; Immunocompromised Host; Infection; Intestines; Investigation; Ions; Iron; Lactobacillus; Lactobacillus reuteri; Lead; Life; Membrane; Membrane Potentials; Metabolic; Metals; Metronidazole; Modeling; Molecular Weight; Morbidity - disease rate; Nature; Organism; Oxidation-Reduction; Patients; Permeability; Pharmaceutical Chemistry; Phase; Probiotics; Production; Property; Protein Biosynthesis; Proteolysis; Public Health; Quantitative Structure-Activity Relationship; Recurrence; Relapse; Reporting; Role; Safety; Selection Criteria; Series; Site; Staging; Structure; Testing; Therapeutic; Therapeutic Uses; Toxin; United States; Vancomycin; Virulent; absorption; analog; antimicrobial; cytotoxicity; design; dimer; gastrointestinal epithelium; in vivo; innovation; killings; meetings; microbial; mortality; novel; older patient; pathogen; preclinical study; prevent; research study; reutericyclin; screening; treatment strategy; trend

DESCRIPTION (provided by applicant): Clostridium difficile infections (CDI) have become more difficult to treat due to the rise of hypervirulent strains that have increased morbidity as well as mortality and the likelihood of persistence and relapse in infected patients. To address the dire need for new anti-difficile agents, we explored the premise that nature utilizes good bacteria (i.e. probiotics), including Lactobacillus spp., to suppress gut pathogens such as C. difficile by producing novel antimicrobials, which were optimized by evolution to the microenvironment of the gut. In this regard, we explored the potential for developing reutericyclin from Lactobacillus reuteri as a natural anti- difficile agent. Probiotics are emerging as alternate treatments for CDI. However, there is ongoing debate on whether live probiotics may be used treat severe CDI, especially in immunocompromised patients. We therefore hypothesize that developing the antimicrobial produced by the probiotic specie would harness one of its natural therapeutic properties for localized killing of C. difficile in the gut, providing a more reliable and efficacious treatment strategy. Application of this concept to our studies on reutericyclin revealed that it has impressive antimicrobial and pharmacological properties for treating CDI. These include: rapid killing of nongrowing, toxin- producing stationary phase C. difficile; a novel mechanism of action specific to the bacterial membrane; a narrow spectrum of activity; lack of cytotoxicity against gut epithelia; stability to proteolysis; ability to achieve high non- absorbed concentrations in gut for killing; a low molecular weight and ease of synthesis that will allow advanced chemical optimization. Importantly, the killing of toxin-producing stationary phase cells is not shown by currently prescribed antibiotics vancomycin and metronidazole, which only kill actively growing C. difficile. We believe that this proposal for developing probiotic-derived reutericylcin derivatives to treat CDI is highly innovative and will be achieved through three iterative aims: (i) Synthesis of an expanded sets of reutericyclin analogs to optimize anti-difficile activity and increase affinity for the membrane target site ; (ii) Lead development and characterization involving the stepwise progression of compounds through three stages of tests that include antimicrobial assessment, pharmacokinetic testing, toxicologic and in vivo efficacy experiments. Compounds meeting the selection criteria of the tests will move onto the next stage such that a lead candidate is obtained with potent in vivo efficacy and excellent safety profile; (iii) Mode of action studies to explore the fundamental antibacterial effects of targeting the clostridial membrane. The long-term goal of this project is to develop optimized lead analogs of probiotic derived reutericyclin that exhibit novel modes of action at the membrane target and have characterized antibiotic properties that would allow their progression into advanced preclinical studies as candidates for treating CDI.

描述（由申请人提供）：由于高毒力菌株的增加，艰难梭菌感染（CDI）变得更加难以治疗，这些菌株增加了感染患者的发病率和死亡率以及持续存在和复发的可能性。为了满足对新型抗艰难梭菌药物的迫切需求，我们探索了这样一个前提：大自然利用包括乳杆菌在内的有益细菌（即益生菌），通过生产新型抗菌剂来抑制艰难梭菌等肠道病原体，这些抗菌剂通过肠道微环境的进化而得到优化。在这方面，我们探索了从罗伊氏乳杆菌中开发罗伊环素作为天然抗艰难梭菌剂的潜力。益生菌正在成为 CDI 的替代疗法。然而，关于活益生菌是否可用于治疗严重 CDI，特别是免疫功能低下患者，目前仍存在争议。因此，我们假设开发益生菌产生的抗菌剂将利用其天然治疗特性之一来局部杀死肠道中的艰难梭菌，从而提供更可靠和有效的治疗策略。将这一概念应用到我们对罗伊环素的研究中表明，它在治疗 CDI 方面具有令人印象深刻的抗菌和药理学特性。这些措施包括： 快速杀死非生长的、产生毒素的稳定期艰难梭菌；细菌膜特有的新作用机制；活动范围狭窄；缺乏针对肠上皮细胞的细胞毒性；蛋白水解稳定性；在肠道内达到高非吸收浓度以进行杀灭的能力；低分子量且易于合成，可实现先进的化学优化。重要的是，目前使用的抗生素万古霉素和甲硝唑并不能杀死产生毒素的静止期细胞，它们只能杀死活跃生长的艰难梭菌。我们相信，开发益生菌衍生的罗伊环素衍生物来治疗 CDI 的提议具有高度创新性，并将通过三个迭代目标来实现：(i) 合成更多的罗伊环素类似物，以优化抗艰难梭菌活性并增加对膜靶位点的亲和力； (ii) 先导化合物的开发和表征，涉及通过三个阶段的测试逐步进展化合物，包括抗菌评估、药代动力学测试、毒理学和体内功效实验。符合测试选择标准的化合物将进入下一阶段，从而获得具有强大体内功效和出色安全性的主要候选药物； (iii) 作用模式研究，探索针对梭菌膜的基本抗菌作用。该项目的长期目标是开发益生菌衍生的罗伊环素的优化先导类似物，这些类似物在膜靶点上表现出新颖的作用模式，并具有抗生素特性，使其能够作为治疗 CDI 的候选药物进入高级临床前研究。