M. tuberculosis Cell Wall Biogenesis; New Drugs; TB-HIV

结核分枝杆菌细胞壁生物发生；

• 批准号: 6890387
• 负责人: Patrick Joseph Brennan
• 金额: $ 3.46万
• 依托单位: COLORADO STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-07-15 至 2008-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6890387
• 关键词: Escherichia coli; Europe; HIV infections; Mycobacterium smegmatis; Mycobacterium tuberculosis; antitubercular agents; arabinose; bacterial genetics; carbohydrate biosynthesis; carbohydrate structure; cell wall; drug design /synthesis /production; enzyme activity; functional /structural genomics; galactans; gene targeting; hexosyltransferase; membrane biogenesis; membrane transport proteins; molecular cloning; peptidoglycan; protein structure function; tuberculosis

DESCRIPTION (provided by applicant): The incidence of HIV-associated tuberculosis has been increasing worldwide since the beginning of the AIDS epidemic, and is expected to rise even further in the future, especially in developing countries. The accelerating and amplifying influence of HIV infection is contributing to the increasing incidence of disease caused by multidrug-resistant strains of Mycobacterium tuberculosis. Development of new drugs against tuberculosis is thus important for control of both of the infections. Mycobacterial cell wall is an attractive target for rational drug design against tuberculosis, due to the fact that it forms a protective, almost impermeable barrier, on the surface of mycobacteria. Some of the most effective drugs currently used for the treatment of TB affect components of its backbone - mycolylarabinogalactan-peptidoglycan (mAGP) complex. Our long-term goal is to identify processes and enzymes involved in the mAGP assembly. Possible AG biosynthetic gene cluster has been recently identified in the genome of M. tuberculosis and thus the specific aims of this grant proposal are: 1. Identify the genes involved in mycobacterial galactan biosynthesis within AG biosynthetic cluster and determine their biological functions via cloning, overexpression and subsequent biochemical characterization. 2. Establish the function of the putative ABC transporter within the AG biosynthetic cluster by way of preparation and phenotypic characterization of the mutants/conditional mutants. The approach will help define one of the more complex pathways in microbial biochemistry and reveal reactions that should be exploitable for drug development. The research will be primarily carried out at Comenius University, Faculty of Natural Sciences in Bratislava, Slovakia in collaboration with Katarina Mikusova, as an extension of the NIH grant A1-18357.

描述（由申请人提供）： 自艾滋病流行病开始以来，与HIV相关的结核病的发生率一直在全球范围内增加，预计将来将在未来，尤其是发展中国家进一步上升。艾滋病毒感染的加速和扩增影响导致疾病的发生率增加，这是由多药结核分枝杆菌的多种抗性菌株引起的。因此，针对结核病的新药开发对于控制两种感染都很重要。分枝杆菌细胞壁是针对结核病的合理药物设计的有吸引力的目标，因为它在分枝杆菌表面形成了保护性，几乎不可渗透的屏障。目前用于治疗结核病的一些最有效的药物会影响其骨干的成分-Mycolylylabinogalactan -Peptidoglycan（MAGP）复合物。我们的长期目标是识别泡泡装配中涉及的过程和酶。最近在结核分枝杆菌的基因组中鉴定出可能的Ag生物合成基因簇，因此该赠款建议的具体目的是：1。确定在Ag生物合成群中分枝杆菌半乳糖生物合成中涉及的基因，并通过croning，过表达，过表达，过表达，生物化学的表征来确定其生物学功能。 2。通过对突变体/条件突变体的制备和表型表征来建立假定的ABC转运蛋白的功能。该方法将有助于定义微生物生物化学中最复杂的途径之一，并揭示应为药物开发而言应该利用的反应。这项研究将主要在斯洛伐克布拉迪斯拉娃的自然科学学院与Katarina Mikusova合作，作为NIH Grant A1-18357的扩展。

项目成果

Synthetic UDP-furanoses as potent inhibitors of mycobacterial galactan biogenesis.

• DOI: 10.1016/j.chembiol.2010.10.014
• 发表时间: 2010-12-22
• 期刊: Chemistry & biology
• 作者: Peltier P;Beláňová M;Dianišková P;Zhou R;Zheng RB;Pearcey JA;Joe M;Brennan PJ;Nugier-Chauvin C;Ferrières V;Lowary TL;Daniellou R;Mikušová K
• 通讯作者: Mikušová K

Biosynthetic origin of the galactosamine substituent of Arabinogalactan in Mycobacterium tuberculosis.

结核分枝杆菌中阿拉伯半乳聚糖的半乳糖胺取代基的生物合成起源。

• DOI: 10.1074/jbc.m110.188110
• 发表时间: 2010
• 期刊: The Journal of biological chemistry
• 作者: Skovierová,Henrieta;Larrouy-Maumus,Gérald;Pham,Ha;Belanová,Martina;Barilone,Nathalie;Dasgupta,Arunava;Mikusová,Katarina;Gicquel,Brigitte;Gilleron,Martine;Brennan,PatrickJ;Puzo,Germain;Nigou,Jérôme;Jackson,Mary
• 通讯作者: Jackson,Mary

Investigation of ABC transporter from mycobacterial arabinogalactan biosynthetic cluster.

• DOI: 10.4149/gpb_2011_03_239
• 发表时间: 2011-09
• 期刊: General physiology and biophysics
• 影响因子: 1.5
• 作者: Dianišková P;Korduláková J;Skovierová H;Kaur D;Jackson M;Brennan PJ;Mikušová K
• 通讯作者: Mikušová K