Broad spectrum Tricyclics GyrB, ParE inhibitors for antibacterial applications

传统的抗菌发现方法是用单一化合物靶向特定的抗菌靶标。这种单一药剂/单一靶标方法通常具有显著的缺点，包括快速出现耐药性和有限的细菌谱。相比之下，靶向细胞内两种蛋白质的抗菌剂的开发提供了更大效力和降低耐药频率的优点。Trius发明了一类新的三环嘧啶并吲哚，其抑制GyrB和帕雷（TriBE抑制剂）。以前发现的GyrB/帕雷抑制剂仅限于革兰氏阳性谱。1许多靶向促旋酶的小分子程序产生具有显著亲脂性的先导化合物，并且受到显著蛋白质结合的阻碍，限制了它们在体内的效用。2然而，我们目前的分子对关键生物防御和临床重要病原体（包括B）表现出广谱抗微生物活性。anthracis，Y. pestis，F.土拉菌和B. B.类鼻疽菌和MRSA、E. coli、A. baumannii，K.肺炎假单胞菌和铜绿假单胞菌。我们已经成功地在几种肺部感染的动物模型中证明了体内疗效，包括MRSA、A.鲍曼不动杆菌和B.假鼻疽TriBE抑制剂计划在不同的开发阶段有几种关键化合物。目前正在评估多种仅静脉内（IV）给药的化合物，以选择作为IND候选药物。此外，在具有口服（PO）给药潜力的早期TriBE化合物方面也取得了进展，如肺炎链球菌肺部感染模型中的疗效所证明。最后，我们正在开发可以IV或PO递送的TriBE前药。当前提案的目的是评价几种TriBE抑制剂（仅IV、PO和前药），以确定对重要ESKAPE和生物防御病原体的抗菌谱（MIC 90），评价动物模型中的疗效，并确定驱动疗效的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。

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.