BACTERIAL DNA POLYMERASES: TARGET FOR NOVEL ANTIBIOTICS

描述（由申请人提供）：I期SBIR的结果提供了一类新的抑制剂，对革兰氏阳性（Gr+）细菌和DNA聚合酶（pol） IIIC和e具有活性，这是建立结构活性关系（SAR）和最佳活性和选择性的理想框架。这类新化合物的抑制机制与苯胺尿嘧啶（AU）化合物的竞争机制和TIBO逆转录酶抑制剂的非竞争机制不同，似乎是“非竞争”抑制。这些数据表明，一个全新的机制参与抑制pol IIIC和E.新家族的化合物显示足够有利的性质（即抑制Gr+ DNA聚合酶和细菌，低体外哺乳动物毒性和选择性的DNA合成），值得进一步的研究和化学修饰，以建立结构活性关系。生物检测将指导SAR的发展。指定的体外先导化合物将在小鼠体内进行一系列实验。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。SAR的开发和体外和体内表征研究是本二期应用的主题。

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.