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

描述（由申请人提供）：肠杆菌科的多重耐药被认为是一种医疗危机。虽然碳青霉烯类抗生素是由这些微生物引起的感染的最常用抗生素之一，但锌基金属碳青霉烯类酶（琥珀B类）引起的碳青霉烯类耐药性是一个日益严重的全球健康问题，可能会削弱这些抗生素在医院和社区环境中的疗效。该耐药酶家族的成员，如NDM-1，与其他耐多药机制混杂在质粒上，并在整个肠杆菌科中迅速传播。现在的问题是，在缺乏临床可用的MBL抑制剂的情况下（即MBL对临床可用的遗留抑制剂他唑巴坦、clavulanic acid和sulbactam具有难治性），MBL如NDM-1可能成为临床环境中主要的碳青霉烯酶。由于目前药物开发中没有MBL抑制剂，因此迫切需要将化合物进展到药物开发管道中，以解决这一日益增长的问题并保护碳青霉烯类。在I期工作中，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，挽救了美罗培南在最近和具有代表性的NDM/VIM产生肠杆菌科临床分离株，铜绿假单胞菌和鲍曼假单胞菌的活性，在小鼠败血症模型中建立了体内疗效，以及与t.i.d.给药美罗培南相容的初步药代动力学。我们还确定了4种潜在的VNRX-5113备用化合物。该II期申请旨在推动这种“同类首创”MBL抑制剂候选物（VNRX-5113）通过ind - enable研究进入新药研究阶段。

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.