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）：耐药细菌感染的管理面临着世界范围的危机。特别是金黄色葡萄球菌、粪肠球菌和粪肠球菌等革兰氏阳性（革兰氏+）细菌对传统抗生素的耐药性日益增强。 该项目重点研究革兰氏+细菌中新描述的 DNA 聚合酶 pol IIIE 的抑制剂，并建立在我们之前在抗菌药物发现中使用 pol IIIC 抑制剂 6-anilinouracils (AU) 的工作中获得的结果的基础上。我们已经从革兰氏+细菌中鉴定出 pol IIIE 的有效先导抑制剂 - N2,7-二取代鸟嘌呤 - 其作为 pol IIIE 的竞争性活性定点抑制剂。基于这些观察，我们将通过以下具体目标来探索抗生素药物： 1.采用平行合成方法合成N2-取代鸟嘌呤、7-取代-N2-取代鸟嘌呤和N2,7-二取代鸟嘌呤； 2. 合成最有效的N2,7-二取代鸟嘌呤的电子等排体 - 3-脱氮、8-氮杂和3-脱氮-8-氮杂鸟嘌呤，预计将成为高效的pol IIIE抑制剂； 3.测定化合物抑制从革兰氏+细菌枯草芽孢杆菌、金黄色葡萄球菌和粪肠球菌以及从革兰氏杆菌大肠杆菌分离的pol IIIE和pol IIIC的能力； 4. 测定化合物对革兰氏+和革兰氏-细菌的作用，以及对人体细胞的细胞毒性； 5.基于目标1-3的结果，设计一种或多种适用于项目II期小鼠感染模型中的药代动力学和药效研究的pol IIIE抑制剂。 Gram+ pol IIIE 的有效抑制将产生耐药性发生率降低的候选抗菌药物。此外，我们的主要抑制剂对来自大肠杆菌的 Gram-pol IIIE 的活性表明了设计源自该支架的真正广谱抗菌化合物的可能性。 拟议的商业应用：一种能够治愈耐药细菌引起的感染的新型抗生素药物可能拥有巨大的市场。 该项目中开发的化合物具有对抗革兰氏+细菌引起的感染的潜在效用，并且由于对多个酶靶点具有活性，因此产生耐药性的可能性较低。 如果此类化合物同时抑制革兰氏+和革兰氏-细菌的靶标，则可以开发出真正的广谱药物。

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