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（由应用程序提供）：�-基于锌的金属 - 乙酰氨基酶（B级B类）赋予的lactam抗性是新兴的全球健康问题1-3。在移动遗传元素上发现了这个酶家族的成员，这些酶的成员在肠杆菌科中迅速传播，并威胁要侵蚀lactam抗生素的未来效用（即青霉素，头孢菌素，头孢菌素，碳酸盐，碳苯甲酸酯）。现在的问题是，在没有临床上可用的MBL抑制剂的情况下，MBL可能成为临床环境中的主要碳青霉酶。由于目前没有制药开发中的MBL抑制剂，因此迫切需要新的计划来解决这一日益增长的问题并保护所有 - lactams的寿命。此阶段I SBIR应用的重点是新型一类化学系列的有效金属 - 乙酰氨酸酶抑制剂（MBLIS）的进步。我们已经产生了细胞活跃的高度复杂的铅化合物，i）报告了对VIM-2（KI为0.002€）和NDM-1的最高亲和力（估计的KI为0.05-0.08€ii），ii），ii）选择性超过5,000倍以上，超过5,000倍的选择性与哺乳动物级别酶的能力，以提高IMIPENEM的重要性。肠杆菌科和假单胞菌属的NDM-1和表达VIM表达临床分离株的活性，以及​​V）对哺乳动物细胞系的活性。这是能够保护NDM-1表达细菌的碳青霉烯的抑制剂系列的第一个报告。该SBIR应用的目的是将当前的先进铅金属酶抑制剂推进到具有潜在的抑制活性的临床前候选候选者对关键MBLS（包括NDM-1和VIM酶）的潜在抑制作用，以帮助保护肠杆菌和PSEUDOMONAS SPP中的Carbonacenem效率。 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 spectra across other subclass B1 MBLs, Maintain selectivity versus mammalian metalloenzymes, increase imepenem rescue capacity in MBL expressing clinical isolates and obtaining proof of in vivo efficiency of a finalist compound in a murine septicemia model感染。成功将触发提交II期建议的提交，该提案包含旨在选择和推进临床前候选人提交的后期铅优化活动。