BACTERIAL DNA POLYMERASES: TARGET FOR NOVEL ANTIBIOTICS

描述(由申请人提供)：第一阶段SBIR的结果提供了一种新型的抑制革兰氏阳性(Gr+)细菌和DNA聚合酶(POL)IIIC和E的活性。这是一个理想的支架，可以在其上建立结构活性关系(SAR)以及最佳活性和选择性。这类化合物的抑制机制不同于苯胺尿嘧啶(AU)类化合物的作用机制是竞争性的，也不同于TIBO逆转录酶抑制剂的作用机制是非竞争性的。结果表明，新化合物家族对PolIIIC和E的抑制作用是一种全新的机制，表现出足够的良好性质(即对Gr+DNA聚合酶和细菌的抑制，对哺乳动物的低体外毒性和对DNA合成的选择性)，值得进一步研究和化学修饰，以建立结构和活性关系。生物检测将指导特区的发展。指定的体外先导化合物将在小鼠身上进行一系列体内实验。这些将包括急性毒性、药代动力学参数和抗生素疗效研究。此外，MicroBiotix将继续筛选和开发新的支架作为DNA复制抑制剂。合成孔径雷达的发展以及体外和体内的表征研究是这一第二阶段应用的主题。

DESCRIPTION (provided by applicant): The results of a Phase I SBIR have provided a novel class of inhibitors active against gram-positive (Gr+) bacteria and against DNA polymerase (pol) IIIC and E. This is an ideal scaffold upon which to build a Structure Activity Relationship (SAR) and optimum activity and selectivity. The mechanism of inhibition of this new class of compounds, unlike the anilinouracil (AU) compounds whose mechanism is competitive, and the TIBO reverse transcriptase inhibitors whose mechanism is noncompetitive, appears to be "uncompetitive" inhibition. The data suggest that an entirely new mechanism is involved in inhibition of pol IIIC and E. The new family of compounds displays enough favorable properties (i.e. inhibition of Gr+ DNA polymerases as well as bacteria, low in vitro mammalian toxicity and selectivity for DNA synthesis) to warrant further investigation and chemical modification in order to develop structure activity relationships. Biological assays will guide the SAR development. Designated in vitro lead compounds will proceed to a series of in vivo experiments performed in mice. These will include acute toxicity, pharmacokinetic parameter and antibiotic efficacy studies. In addition, Microbiotix will continue to screen for and develop new scaffolds as DNA replication inhibitors. The SAR development and in vitro and in vivo characterization studies are the subject of this Phase II application.