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

项目摘要： 耐万古霉素肠球菌(VRE)是医院获得性耐药的第二大原因 美国感染(HAI)，触发疾病控制和预防中心将VRE归类为 严重的医疗保健威胁。尽管VRE感染的流行率和严重性有限，但 可供治疗的有效治疗选择。此外，现有的药物也是有害的。 到正常的肠道微生物区系，最终导致微生物失衡的问题循环，称为 生态失调，肠球菌首先利用这一点。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，而不需要 破坏正常肠道菌群的动态平衡。不同于昂贵和耗时的新药过程 发现，药物再利用是一种减少药物创新所需时间、成本和风险的新方法。 本申请中提出的研究建立在强效和窄谱抗菌剂的发现基础上 FDA批准的药物碳酸酐酶抑制剂(CAI)(乙酰唑胺、多唑胺、 布林唑胺、乙氧唑胺、甲唑胺和二氯苯酰胺)，在适用的临床范围内，针对 高度耐多药的肠球菌，包括VRE。我们已经在体外和体内证明了cais 优于首选药物利奈唑胺，可用于治疗严重的VRE感染和VRE 在不损害肠道微生物区系的情况下非殖民化。此外，我们还发现了一种新的抗微生物靶标。 针对肠球菌，可在未来筛选新的抑制性支架活动中使用。我们的 团队已经着手进行药物化学优化，并提高了支架相对于VRE的效力 提高570倍(对于最有效的类似物，最低抑菌浓度=0.007微克/毫升)，同时保持正常的抗菌活性 肠道微生物区系。我们建议继续对铅进行优化，并评估在不同VRE小鼠体内的疗效 模型还评估了新型缓蚀剂的安全性和PK曲线，以支持未来的铅选择和 研究性新药赋能研究。

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.