Novel Metallo-beta-lactamase Inhibitors

新型金属-β-内酰胺酶抑制剂

• 批准号: 8334617
• 负责人: Bin Liu
• 金额: $ 29.4万
• 依托单位: VENATORX PHARMACEUTICALS, INC.
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-09-21 至 2013-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8334617
• 关键词: Address; Affinity; Amber; Antibiotics; Applications Grants; Bacteria; Biochemical; Carbapenems; Cell Line; Cells; Cephalosporins; Chemicals; Chemistry; Clinical; Collection; Community Hospitals; Development; Drug Kinetics; Engineering; Enterobacteriaceae; Enzymes; Escherichia coli; Family; Family member; Future; Generic Drugs; Goals; Gram-Negative Bacteria; Gram-Negative Bacterial Infections; Hospitals; Imipenem; Incidence; Infection; Lactamase; Lactams; Lead; Longevity; Mammalian Cell; Medical; Mobile Genetic Elements; Modeling; Monobactams; Mus; Penicillins; Pharmacologic Substance; Phase; Predisposition; Pseudomonas; Pseudomonas aeruginosa; Reporting; Resistance; Septicemia; Series; Small Business Innovation Research Grant; Staging; Structure-Activity Relationship; Variant; Zinc; analog; base; beta-Lactamase; candidate selection; carbapenem resistance; community setting; cytotoxicity; design; global health; improved; in vivo; inhibitor/antagonist; lead series; metalloenzyme; novel; pre-clinical; pressure; prospective; prototype; success

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.

描述（由申请人提供）：锌基金属内酰胺酶（琥珀B类）引起的内酰胺耐药性是一个新兴的全球健康问题1-3。该酶家族的成员，如NDM-1，被发现在肠杆菌科的移动遗传元件上，这些元件正在迅速传播，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主要的碳青霉烯酶。由于目前在药物开发中没有MBL抑制剂，因此迫切需要采取新的举措来解决这一日益严重的问题，并保护所有内酰胺类药物的使用寿命。这项I期SBIR申请的重点是推进一种新型的一流化学系列有效的金属-内酰胺酶抑制剂（MBLIs）。我们已经生成了具有细胞活性的高可溶性高级先导化合物，其具有i)对VIM-2 （Ki值为0.002¿M）和NDM-1 （Ki值估计为0.05- 0.08¿M）的最高亲和力，ii)相对于哺乳动物金属酶的选择性大于5000倍，iii)在大肠杆菌中提高亚胺培南活性高达128倍的能力，iv)在肠杆菌科和假单胞菌中表达NDM-1和vim的临床分离株中具有显著的亚胺培南拯救活性。5)对哺乳动物细胞系无细胞毒性。这是第一个能够在表达NDM-1的细菌中保护碳青霉烯的抑制剂系列的报道。该SBIR申请的目标是将现有的先进铅金属-内酰胺酶抑制剂发展为临床前候选“决赛者”，具有对关键MBLs（包括NDM-1和VIM酶）的有效抑制活性，以帮助保护碳青霉烯在肠杆菌科和假单胞菌中的功效。在申请的2年时间框架内，我们打算通过提高对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的临床分离株亚胺培南的拯救能力，并在小鼠败血症感染模型中获得最终化合物的体内功效证明。成功将触发提交II期提案，其中包含针对选择和推进临床前候选药物提交IND的后期Lead优化活动。