LY256: A novel and potent antibiotic for treating Clostridium difficile infection

LY256：一种治疗艰难梭菌感染的新型强效抗生素

• 批准号: MR/S019103/1
• 负责人: Weng Chan
• 金额: $ 220.33万
• 依托单位: University of Nottingham
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2019
• 资助国家: 英国
• 起止时间: 2019 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FS019103%2F1
• 关键词: LY256; novel; potent; antibiotic; treating

Clostridium difficile infection (CDI) is a serious global public health threat, and is associated with significant morbidity, mortality and healthcare resource utilisation. Recent estimates suggest over 400,000 cases of CDI occur annually in Europe, and nearly half a million CDI cases and over 29,000 deaths reported in the US in 2011/2015. However, we also know that many cases are missed due to the lack of testing or use of sub-optimal diagnostics. Approximately 20-30% of patients experience disease recurrence, with around a third of patients presenting with severe CDI at the recurrent episode. For those with more than one previous recurrence, the risk of further recurrences increases to 40-65%. The effectiveness of a former mainstay of CDI treatment, metronidazole, is now compromised and antimicrobial resistant strains are emerging. The US CDC has recently classified this "superbug" among the serious immediate antibiotic-resistant infectious public health threats that require immediate and aggressive action (https://www.cdc.gov/drugresistance/biggest_threats.html). There is a real unmet need to develop new narrow-spectrum antibiotics that can prevent relapse of CDI, and thus reduce overall high healthcare-related expenditure on this infection, which can exceed £8,000 per patient.In this project, we propose to further develop a promising new pre-clinical lead compound developed by researchers at the University of Nottingham. This drug 'LY256' has shown targeted (the majority of normal gut flora are insensitive to LY256) and potent antimicrobial activity against multiple strains of Clostridium difficile. In two different small animal models of CDI, orally administered drug given twice daily for 5 days was effective in treating CDI. During the project, individual work packages aligned to specific checkpoints will (i) develop methods for large scale manufacture of LY256, (ii) determine effective orally administered doses for treatment of both primary and recurrent infection using small animal and human in vitro gut models of CDI, and (iii) investigate if this new anti-C. difficile therapy can be combined with probiotic treatment approaches to exert an even greater therapeutic response. Specifically, attention will focus on combining a well-established gut commensal micro-organism with LY256. Our proposed solution may be immensely important in treating CDI without the use of more rudimentary approaches like faecal microbiota transplantation (FMT) or other less targeted antimicrobial strategies. LY256 can kill vegetative cells, has targeted activity against C. difficile, and is poorly absorbed from the gastrointestinal tract, making it an ideal candidate for further development.

艰难梭菌感染（CDI）是一种严重的全球公共卫生威胁，与显著的发病率、死亡率和医疗资源利用相关。最近的估计表明，欧洲每年发生超过400，000例CDI病例，2011/2015年美国报告了近50万例CDI病例和超过29，000例死亡。然而，我们也知道，由于缺乏测试或使用次优诊断，许多病例被遗漏。大约20-30%的患者经历疾病复发，其中大约三分之一的患者在复发发作时表现为重度CDI。对于那些有一个以上的复发，进一步复发的风险增加到40- 65%。CDI治疗的前支柱甲硝唑的有效性现在受到损害，并且正在出现耐药性菌株。美国疾病控制和预防中心最近将这种“超级细菌”归类为需要立即采取积极行动的严重的即时抗药性传染性公共卫生威胁（https：//www.cdc.gov/drugresistance/biggest_threats.html）。有一个真实的未满足的需求，开发新的窄谱抗生素，可以防止复发的CDI，从而减少整体高医疗保健相关的支出对这种感染，这可能超过£8,000每名patient.In这个项目中，我们建议进一步开发一个有前途的新的临床前先导化合物开发的研究人员在诺丁汉大学。该药物“LY 256”已显示出针对多种艰难梭菌菌株的靶向（大多数正常肠道植物群对LY 256不敏感）和有效的抗微生物活性。在两种不同的小动物CDI模型中，口服给药，每日两次，持续5天，可有效治疗CDI。在该项目期间，与特定检查点一致的各个工作包将（i）开发用于大规模生产LY 256的方法，（ii）使用CDI的小动物和人体外肠道模型确定治疗原发性和复发性感染的有效口服给药剂量，以及（iii）研究这种新的抗C抗体。艰难梭菌治疗可以与益生菌治疗方法组合以发挥更大的治疗反应。具体而言，注意力将集中在将良好建立的肠道微生物与LY 256相结合。我们提出的解决方案在治疗CDI方面可能非常重要，而无需使用更基本的方法，如粪便微生物群移植（FMT）或其他针对性较低的抗菌策略。LY 256能杀死营养细胞，对C.艰难梭菌，并且从胃肠道吸收不良，使其成为进一步开发的理想候选物。