Broad spectrum Tricyclics GyrB, ParE inhibitors for antibacterial applications

用于抗菌应用的广谱三环 GyrB、ParE 抑制剂

• 批准号: 9243957
• 负责人: KENNETH BARTIZAL
• 金额: $ 53.39万
• 依托单位: RBHS-NEW JERSEY MEDICAL SCHOOL
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/9243957
• 关键词: Acinetobacter baumannii; Alpha Cell; Animal Model; Anti-Bacterial Agents; Antibiotics; Bacillus anthracis; Bacteria; Bacterial Drug Resistance; Binding Proteins; Bioterrorism; Burkholderia mallei; Burkholderia pseudomallei; Clinical; Data; Development; Ear; Engineering; Enterococcus faecium; Escherichia coli; Francisella tularensis; Goals; Infection; Intravenous; Klebsiella pneumonia bacterium; Lead; Lung; Modeling; Multi-Drug Resistance; Oral; Oral Administration; Pneumonia; Prodrugs; Proteins; Pseudomonas aeruginosa; Resistance; Staphylococcus aureus; Streptococcus pneumoniae; Testing; Therapeutic; Thigh structure; Tricyclic GyrB/ParE Inhibitors; Yersinia pestis; antimicrobial; bacterial resistance; base; biodefense; combat; in vivo; inhibitor/antagonist; innovation; interest; lipophilicity; methicillin resistant Staphylococcus aureus; novel; pathogen; preclinical development; programs; resistance frequency; small molecule; targeted agent; weapons

The traditional approach to antibacterial discovery is to target a specific antibacterial target with a single compound. This single agent/single target approach often suffers from significant drawbacks including the rapid emergence of resistance and limited bacterial spectrum. In contrast, the development of an antibacterial agent that targets two proteins within a cell provides advantages of greater potency and reduced resistance frequency. Trius has invented a novel class of Tricyclic pyrimidoindoles that inhibit GyrB and ParE (TriBE inhibitors). Previously discovered GyrB/ParE inhibitors were limited to Gram-positive profiles. 1 Many small molecule programs targeting gyrase generated lead compounds with significant lipophilicity, and were hampered by significant protein binding, limiting their utility in vivo.2 However, our current molecules demonstrate broad spectrum antimicrobial activity against key biodefense and clinically important pathogens including B. anthracis, Y. pestis, F. tularensis and B. pseudomallei as well as MRSA, E. coli, A. baumannii, K. pneumoniae and P. aeruginosa. We have successfully demonstrated in vivo efficacy in several animal models of lung infections including MRSA, A. baumannii and B. pseudomallei. The TriBE inhibitor program has several key compounds at different stages of development. Multiple intravenous (IV)-only compounds are currently being evaluated for selection as an IND candidate. In addition, progress has been made on earlier stage TriBE compounds that have the potential for oral (PO) administration, as demonstrated by efficacy in a Streptococcus pneumoniae lung infection model. Finally, we are developing TriBE prodrugs that can be delivered IV or PO. The goal ofthe current proposal is to evaluate several TriBE inhibitors (IV-only, PO and prodrugs) to determine the antimicrobial spectrum (MIC90) against important ESKAPE and biodefense pathogens, to evaluate efficacy in animal models, and to identify the PK/PD parameters that drive efficacy. These data will be used to select the final candidates for preclinical development for both IV and PO treatment.

抗菌发现的传统方法是用单一化合物针对特定的抗菌靶标。这种单剂/单靶点方法通常存在明显的缺点，包括耐药性的迅速出现和有限的细菌谱。相比之下，开发针对细胞内两种蛋白质的抗菌剂具有更强的效力和更低的耐药频率的优点。 Trius 发明了一类新型三环嘧啶吲哚，可抑制 GyrB 和 ParE（TriBE 抑制剂）。之前发现的 GyrB/ParE 抑制剂仅限于革兰氏阳性菌。 1 许多针对旋转酶的小分子程序产生具有显着亲脂性的先导化合物，并受到显着蛋白质结合的阻碍，从而限制了它们在体内的实用性。 2 然而，我们目前的分子表现出针对关键生物防御和临床重要病原体的广谱抗菌活性，包括炭疽芽孢杆菌、鼠疫杆菌、土拉热杆菌和类鼻疽杆菌以及 MRSA、大肠杆菌、鲍曼不动杆菌、肺炎克雷伯菌和铜绿假单胞菌。我们已在多种肺部感染动物模型中成功证明了体内功效，包括 MRSA、鲍曼不动杆菌和类鼻疽杆菌。 TriBE 抑制剂计划有几种处于不同开发阶段的关键化合物。目前正在评估多种仅静脉注射 (IV) 的化合物，以选择作为 IND 候选药物。此外，早期 TriBE 化合物也取得了进展，具有口服 (PO) 给药的潜力，肺炎链球菌肺部感染模型的功效证明了这一点。最后，我们正在开发可以静脉注射或口服给药的 TriBE 前药。当前提案的目标是评估几种 TriBE 抑制剂（仅 IV、PO 和前药），以确定针对重要 ESKAPE 和生物防御病原体的抗菌谱 (MIC90)，评估动物模型中的功效，并确定驱动功效的 PK/PD 参数。这些数据将用于选择 IV 和 PO 治疗临床前开发的最终候选药物。