Repurposing novel selective drugs for treatment and decolonization of vancomycin resistant enterococci

重新利用新型选择性药物治疗万古霉素耐药肠球菌并使其去定植

• 批准号: 10332029
• 负责人: Mohamed Seleem
• 金额: $ 62.07万
• 依托单位: VIRGINIA POLYTECHNIC INST AND ST UNIV
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-19 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10332029
• 关键词: Repurposing; novel; selective; drugs; treatment

Project Abstract: Vancomycin-resistant enterococci (VRE) is the second leading cause of drug-resistant hospital-acquired infections (HAIs) in the US, triggering the Centers for Disease Control and Prevention to classify VRE as a serious healthcare threat. Despite the prevalence and severity of VRE infections, there are limited number of effective therapeutic options available for treatment. Moreover, the drugs that are available are also detrimental to the normal gut microbiota ultimately contributing the problematic cycle of microbial imbalance known as dysbiosis, which enterococcus takes advantage of in the first place. Thus, there is a significant need for a treatment that can be used to clear both symptomatic and asymptomatic enterococcus colonization without damaging the homeostasis of normal gut flora. Unlike the costly and time-consuming process of de novo drug discovery, drug repurposing is a novel method to reduce the time, cost and risk associated with drug innovation. Studies proposed in this application build upon discoveries of the potent and narrow spectrum antimicrobial activity of the FDA-approved drugs, carbonic anhydrase inhibitors (CAIs) (acetazolamide, dorzolamide, brinzolamide, ethoxzolamide, methazolamide, and dichlorphenamide), in an applicable clinical range, against highly multidrug-resistant enterococci, including VRE. We have demonstrated both in vitro and in vivo that CAIs are superior to drug of choice, linezolid, and can be used for treatment of serious VRE infections as well as VRE decolonization without harming gut microbiota. In addition, we were able to identify a novel antimicrobial target specific for enterococci that could be exploited in future screening campaigns for new inhibitory scaffolds. Our team has embarked upon medicinal chemistry optimization and improved the potency of the scaffold versus VRE by 570-fold (MIC = 0.007 µg/ml for most potent analog) while maintaining no antibacterial activity against normal gut microbiota. We propose to continue lead optimization and assess the in vivo efficacy in various VRE mouse models as well evaluate the novel inhibitor’s safety and PK profiles to support future lead selection and investigational new drug enabling studies.

项目摘要： 耐万古霉素肠球菌（VRE）是耐药的医院获得性肺炎的第二大原因。 在美国的感染（HAI），触发疾病控制和预防中心将VRE归类为 严重的健康威胁。尽管VRE感染的患病率和严重性， 有效的治疗选择。而且，现有的药物也是有害的 正常的肠道微生物群，最终导致微生物不平衡的问题循环， 肠球菌首先利用的是生态失调。因此，非常需要一种 可用于清除有症状和无症状肠球菌定植的治疗， 破坏正常肠道植物群的体内平衡。与从头药物治疗的昂贵和耗时的过程不同， 药物再利用是一种新的方法，可以减少与药物创新相关的时间、成本和风险。 本申请中提出的研究建立在发现强效和窄谱抗菌剂的基础上 FDA批准的药物碳酸酐酶抑制剂（CAIs）（乙酰唑胺，多佐胺， 布林佐胺、乙氧唑胺、醋甲唑胺和双氯苯那胺），在适用的临床范围内， 高度耐多药肠球菌，包括VRE。我们已经在体外和体内证明， 上级首选药物利奈唑胺，可用于治疗严重VRE感染以及VRE 去殖民化而不损害肠道微生物群。此外，我们能够确定一种新的抗菌靶标， 特异性肠球菌，可以利用在未来的筛选活动，新的抑制性支架。我们 研究小组已经开始进行药物化学优化，并提高了支架与VRE的效力 570倍（最有效类似物的MIC = 0.007 µg/ml），同时对正常人无抗菌活性 肠道微生物群我们建议继续优化电极导线，并在各种VRE小鼠中评估体内疗效 模型以及评估新型抑制剂的安全性和PK特征，以支持未来的铅选择， 研究性新药启动研究。