Phase II SBIR: Responding to NDM-1 - Advancement of a new MBL inhibitor to IND

描述(申请人提供)：肠杆菌科多药耐药被认为是一种医疗危机。虽然碳青霉烯类抗生素是治疗由这些细菌引起的感染最常用的抗生素之一，但锌基金属碳青霉烯酶(琥珀B类)所产生的碳青霉烯类耐药性是一个日益严重的全球健康问题，有可能侵蚀这些抗生素在医院和社区的疗效。这个耐药酶家族的成员，如NDM-1，在具有其他耐药机制的混杂质粒上被发现，并在肠杆菌科中迅速传播。现在的担忧是，在缺乏临床可用的MBL抑制剂的情况下(即MBL对临床上可用的传统抑制剂他唑巴坦、克拉维酸和舒巴坦无效)，MBL如NDM-1可能成为临床上的主要碳青霉烯酶。由于目前在药物开发中没有MBL抑制剂，迫切需要将化合物进展到药物开发流水线中，以解决这一日益严重的问题并保护碳青霉烯类抗生素。在第一阶段的工作中，我们确定了一种开发前候选药物VNRX-5113，达到或超过了既定的成功标准，包括对NDM-1和VIM MBLS的有效和选择性抑制活性，挽救了最近产生NDM/VIM的肠杆菌科临床菌株、铜绿假单胞菌和鲍曼不动杆菌的美罗培南活性，这些菌株在小鼠败血症模型中建立了体内疗效，并与T.I.D.兼容。用美罗培南给药。我们还确定了4种可能的VNRX-5113备用化合物作为应急措施。第二阶段的应用程序努力推动这一“第一类”MBL抑制剂候选(VNRX-5113)通过IND使能研究到研究性新药备案。

DESCRIPTION (provided by applicant): Multi-drug resistance in Enterobacteriaceae is regarded as a healthcare crisis. While carbapenems are among the most prescribed antibiotics for infections caused by these organisms, carbapenem resistance conferred by zinc-based metallo-carbapenemases (Amber Class B) is a growing global health concern that threatens to erode the efficacy of these antibiotics both in the hospital and community settings. Members of this family of resistance enzymes such as NDM-1 are found on promiscuous plasmids with other MDR resistance mechanisms, and are rapidly spreading throughout Enterobacteriaceae. The concern now is that, in the absence of clinically available MBL inhibitors (i.e. MBLs are refractory to clinically available legacy inhibitors tazobactam, clavulanic acid and sulbactam), MBLs such as NDM-1 could become the dominant carbapenemases in clinical settings. As there are currently no MBL inhibitors in pharmaceutical development, there is an urgent need to progress compounds into the drug development pipeline to address this growing issue and safeguard carbapenems. In the Phase I work, we identified a pre-development candidate, VNRX-5113, meeting or exceeding established success criteria including potent and selective inhibitory activity against NDM-1 and VIM MBLs, rescue of Meropenem activity in recent and representative NDM/VIM-producing clinical isolates of Enterobacteriaceae, P. aeruginosa and A. baumannii, established in vivo efficacy in a murine septicemia model and preliminary pharmacokinetics compatible with t.i.d. dosing with Meropenem. We also identified 4 potential backup compounds to VNRX-5113 as contingencies. The Phase II application endeavors to drive this "first in class" MBL inhibitor candidate (VNRX-5113) through IND-enabling studies to an Investigational New Drug filing.