DNA Polymerase IIIE, A New Antibiotic Target

DNA 聚合酶 IIIE，新的抗生素靶点

• 批准号: 6548864
• 负责人: George E Wright
• 金额: $ 30.71万
• 依托单位: GLSYNTHESIS, INC.
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-07-01 至 2003-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6548864
• 关键词: Bacillus subtilis; DNA directed DNA polymerase; Enterococcus; Staphylococcus aureus; antibiotics; chemical synthesis; clinical research; drug design /synthesis /production; drug resistance; drug screening /evaluation; gram positive bacteria; guanine; host organism interaction; pharmacokinetics

DESCRIPTION (provided by applicant): There is a worldwide crisis in management of drug-resistant bacterial infections. In particular Gram-positive (Gram+) bacteria such as Staphylococcus aureus, Enterococcus fecalis and Enterococcus fecium are increasingly resistant to traditional antibiotics. This project focuses on inhibitors of a newly described DNA polymerase in Gram+ bacteria, pol IIIE, and builds upon previous results obtained from our work with inhibitors of pol IIIC, the 6-anilinouracils (AUs), in antibacterial drug discovery. We have identified potent lead inhibitors of pol IIIE from Gram+ bacteria - N2,7-disubstituted guanines - that act as competitive, active site-directed inhibitors of pol IIIE. Based on these observations we will pursue antibiotic drug discovery through these specific aims: 1. to use parallel synthesis methods to synthesize N2-substituted guanines, 7-substituted-N2-substituted guanines, and N2,7-disubstituted guanines; 2. to synthesize isosteres of the most potent N2,7-disubstituted guanines - 3-deaza, 8-aza and 3-deaza-8-aza guanines predicted to be highly potent pol IIIE inhibitors; 3. to assay compounds for their capacity to inhibit pol IIIE and pol IIIC isolated from the Gram+ bacteria B. subtilis, S. aureus, and E. fecalis, and from the Gram- bacterium E. coli; 4. to assay compounds against Gram+ and Gram- bacteria, and for cytotoxicity against human cells; 5. to design, based on the results of aims 1-3, one or more pol IIIE inhibitors suitable for pharmacokinetic and efficacy studies in mouse infection models during phase II of the project. Potent inhibition of Gram+ pol IIIE will lead to candidate antibacterials with reduced incidence of resistance. In addition, activity against the Gram- pol IIIE from E. coli by our lead inhibitor indicates the possibility of designing a truly broad spectrum antibacterial compound derived from this scaffold. PROPOSED COMMERCIAL APPLICATION: A new antibiotic drug capable of curing infections caused by drug-resistant bacteria can have a significant market. The compounds developed in this project have potential utility against infections caused by Gram+ bacteria, and, by virtue of being active against more than one enzymatic target, will have a low tendency to develop resistance. Truly broad spectrum drugs may be developed if such compounds inhibit targets in both Gram+ and Gram- bacteria.

描述（由申请人提供）：在耐药细菌感染的管理方面存在全球危机。尤其是革兰氏阳性（Gram+）细菌，例如金黄色葡萄球菌，卵子肠球菌和粪肠球菌越来越对传统抗生素具有抗药性。 该项目的重点是在革兰氏+细菌（POLIIE）中新描述的DNA聚合酶的抑制剂，并建立在我们与Pol Iiic抑制剂（6-氨基核酸酚（AUS））抑制剂中获得的先前结果，在抗细菌药物发现中。我们已经确定了革兰氏+细菌的POL IIIE的有效铅抑制剂-n2,7-二取代的鸟嘌呤，它们是POL IIIE的竞争性，主动地点指导的抑制剂。根据这些观察，我们将通过这些特定目的进行抗生素药物发现： 1。使用平行合成方法来合成N2取代的鸟嘌呤，7-取代的N2取代的鸟嘌呤和N2,7-二取代的鸟嘌呤； 2。合成最有效的N2,7-脱取代的鸟嘌呤的等值线 - 3- deaza，8-aza和3-Deaza-8-8-aza Guanines被预计是高度有效的POL IIIE抑制剂； 3。分析化合物，以抑制从克+细菌中分离出的pol IIIE和pol IIIC。 4。测定针对革兰氏+和革兰氏菌的化合物，以及针对人类细胞的细胞毒性； 5。设计，基于目标1-3的结果，一个或多个POL IIIE抑制剂适用于该项目II期期间小鼠感染模型中适用于药代动力学和功效研究。 对革兰氏+ POL IIIE的有效抑制作用将导致抗菌抗菌抗菌剂，其抗性发生率降低。此外，我们的铅抑制剂对大肠杆菌的革兰氏阴性IIIE的活性表明，有可能设计从该支架中得出的真正宽光谱抗菌化合物。 拟议的商业应用：一种能够治愈由耐药细菌引起的能够治愈感染的新型抗生素药物可以具有重要的市场。 该项目中开发的化合物具有针对革兰氏+细菌引起的感染的潜在效用，并且由于对超过一个酶促靶标的活跃，将具有较低的发展抗性趋势。 如果这种化合物抑制革兰氏+和革兰氏菌的靶标，则可以开发真正的广谱药物。

项目成果

Clostridium difficile DNA polymerase IIIC: basis for activity of antibacterial compounds.

艰难梭菌 DNA 聚合酶 IIIC：抗菌化合物活性的基础。

• DOI: 10.2174/157340811798807597
• 发表时间: 2011
• 期刊: Current enzyme inhibition
• 作者: Torti,Andrea;Lossani,Andrea;Savi,Lida;Focher,Federico;Wright,GeorgeEdward;Brown,NealCurtis;Xu,Wei-Chu
• 通讯作者: Xu,Wei-Chu

Active site directed inhibitors of replication-specific bacterial DNA polymerases.

复制特异性细菌 DNA 聚合酶的活性位点定向抑制剂。

• DOI: 10.1016/j.bmcl.2004.11.016
• 发表时间: 2005
• 期刊: Bioorganic & medicinal chemistry letters.
• 作者: Wright,GeorgeE;Brown,NealC;Xu,Wei-Chu;Long,Zheng-Yu;Zhi,Chengxin;Gambino,JosephJ;Barnes,MarjorieH;Butler,MichelleM
• 通讯作者: Butler,MichelleM

7-Alkyl-N(2)-substituted-3-deazaguanines. Synthesis, DNA polymerase III inhibition and antibacterial activity.

7-烷基-N(2)-取代-3-脱氮鸟嘌呤。

• DOI: 10.1016/j.bmcl.2011.05.093
• 发表时间: 2011
• 期刊: Bioorganic & medicinal chemistry letters
• 影响因子: 2.7
• 作者: Xu,Wei-Chu;Wright,GeorgeE;Brown,NealC;Long,Zheng-Yu;Zhi,Cheng-Xin;Dvoskin,Sofya;Gambino,JosephJ;Barnes,MarjorieH;Butler,MichelleM
• 通讯作者: Butler,MichelleM