Novel Metallo-beta-lactamase Inhibitors

描述（由申请人提供）：锌基金属-β-内酰胺酶（琥珀色B类）引起的β-内酰胺耐药性是一个新出现的全球健康问题1 -3。在移动的遗传元件上发现了该酶家族的成员，如NDM-1，这些基因元件在肠杆菌科中迅速传播，并威胁到未来在医院和社区环境中使用内酰胺类抗生素（即青霉素类、头孢菌素类、碳青霉烯类）1，5，6。现在的问题是，在缺乏临床可用的MBL抑制剂的情况下，MBL可能成为临床环境中的主要碳青霉烯酶。由于目前在药物开发中没有MBL抑制剂，因此迫切需要新的举措来解决这一日益严重的问题并保护所有内酰胺的寿命。该I期SBIR申请的重点是一种新型的一流化学系列强效金属-β-内酰胺酶抑制剂（MBLI）的进展。我们已经产生了具有细胞活性的高度可溶的高级先导化合物，i）对Vim-2（Ki为0.002 <$M）和NDM-1（估计Ki为0.05- 0.08 <$M）具有最高的亲和力，ii）对哺乳动物金属酶的选择性大于5，000倍，iii）在大肠杆菌中将亚胺培南活性提高高达128倍的能力。iv）在肠杆菌科和假单胞菌属的表达NDM-1和VIM的临床分离株的集合中显著的亚胺培南拯救活性，和v）对哺乳动物细胞系无细胞毒性。这是第一次报道能够在NDM-1表达细菌中保护碳青霉烯的抑制剂系列。该SBIR申请的目标是将当前的高级铅金属-β-内酰胺酶抑制剂进展为临床前候选“入围者”，其对关键MBL（包括NDM-1和Vim酶）具有强效抑制活性，以帮助保护碳青霉烯在肠杆菌科和假单胞菌属中的疗效。在申请的2年时间范围内，我们打算通过增加对NDM-1和VIM变体的效力来推进该系列的化学优化，评估其他B1亚类MBL的MBL谱，保持对哺乳动物金属酶的选择性，增加表达MBL的临床分离株中的亚胺培南拯救能力，并获得最终化合物在鼠败血症感染模型中的体内疗效的证据。成功将触发提交II期提案，其中包含旨在选择和推进临床前候选IND提交的后期电极导线优化活动。

DESCRIPTION (provided by applicant): ¿-lactam resistance conferred by zinc-based metallo-¿-lactamases (Amber Class B) is an emerging global health problem1-3. Members of this family of enzymes such as NDM-1 are found on mobile genetic elements which are rapidly spreading in Enterobacteriaceae and threaten to erode the future utility of the ¿- lactam antibiotics (i.e. penicillins, cephalosporins, carbapenems) both in hospital and community settings1,5,6. The concern now is that, in the absence of clinically available MBL inhibitors, MBLs could become the dominant carbapenemases in clinical settings. As there are currently no MBL inhibitors in pharmaceutical development, there is an urgent need for new initiatives to address this growing issue and protect the lifespan of all ¿-lactams. This Phase I SBIR Application focuses on the advancement of a novel first-in-class chemical series of potent metallo-¿-lactamase inhibitors (MBLIs). We have generated cell active highly soluble advanced lead compounds with i) the highest reported affinity for VIM-2 (Ki of 0.002 ¿M) and NDM-1 (estimated Ki of 0.05- 0.08 ¿M), ii) greater than 5,000-fold selectivity versus mammalian metalloenzymes, iii) the ability to improve imipenem activity by up to 128-fold in E. coli, iv) significant imipenem rescue activity in a collection of NDM-1 and VIM-expressing clinical isolates of Enterobacteriaceae and Pseudomonas spp., and v) no cytotoxicity against mammalian cell lines. This is the first report of an inhibitor series capable of protecting a carbapenem in NDM-1 expressing bacteria. The goal of this SBIR application is to progress current Advanced Lead Metallo-¿-Lactamase inhibitors to Preclinical Candidate "Finalists" possessing potent inhibitory activity towards key MBLs including NDM-1 and VIM enzymes to help protect carbapenem efficacy in Enterobacteriaceae and Pseudomonas spp. During the 2-year timeframe of the Application, we intend to advance the chemical optimization of this series by increasing potency to NDM-1 and VIM-variants, assess MBL spectrum across other subclass B1 MBLs, maintain selectivity versus mammalian metalloenzymes, increase imipenem rescue capacity in MBL expressing clinical isolates and obtain proof of in vivo efficacy of a finalist compound in a murine septicemia model of infection. Success will trigger the submission of a phase II proposal containing late stage Lead optimization activities directed at selecting and advancing a Preclinical Candidate to IND submission.