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(申请人提供)：耐药细菌感染的管理存在世界性危机。尤其是革兰氏阳性(Gram+)细菌，如金黄色葡萄球菌、粪肠球菌和粪肠球菌对传统抗生素的耐药性越来越强。 该项目专注于革兰氏阳性细菌中一种新描述的DNA聚合酶的抑制剂PolIIIe，并建立在我们之前在抗菌药物发现中使用PolIIIC的抑制剂6-苯胺尿嘧啶(AU)所获得的结果的基础上。我们已经从革兰氏阳性细菌中鉴定出了有效的PolIIe的先导抑制剂--N2，7-二取代鸟嘌呤--它们是PolIIe的竞争性、活性位点定向抑制剂。基于这些观察，我们将通过以下具体目标进行抗生素药物的发现： 1.采用平行合成方法合成N_2-取代鸟嘌呤、7-取代-N_2-N_2-取代鸟嘌呤和N，7-二取代鸟嘌呤； 2.合成最有效的N，7-二取代鸟嘌呤-3-去氮基、8-氮杂基和3-去氮杂-8-氮杂鸟嘌呤类化合物； 3.测定化合物对从革兰氏阳性菌枯草杆菌、金黄色葡萄球菌、粪便革兰氏杆菌和革兰氏杆菌分离出的PolIIe和PolIIc的抑制能力； 4.测定化合物对革兰氏阳性菌和革兰氏阴性杆菌的抗菌活性，以及对人体细胞的细胞毒性； 5.根据AIMS 1-3的结果，在项目第二阶段设计一种或多种PolIIIe抑制剂，适合在小鼠感染模型中进行药代动力学和疗效研究。 对Gram+PolIIIe的有效抑制将导致候选抗菌药的出现，减少耐药性的发生率。此外，我们的先导抑制剂对来自大肠杆菌的革兰氏IIIe的活性表明，有可能从这种支架中设计出真正广谱的抗菌化合物。 拟议的商业应用：一种能够治疗由耐药细菌引起的感染的新型抗生素药物可能有很大的市场。在这个项目中开发的化合物对革兰氏+细菌引起的感染具有潜在的实用价值，并且由于对多个酶靶标具有活性，将具有较低的抗药性倾向。如果这种化合物同时抑制革兰氏阳性菌和革兰氏菌的靶标，就可能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