Structure-based Discovery of Critical Vulnerabilities of Mycobacteria

基于结构的分枝杆菌关键漏洞发现

• 批准号: 10456888
• 负责人: JAMES C SACCHETTINI
• 金额: $ 238.76万
• 依托单位: TEXAS A&M AGRILIFE RESEARCH
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-09-01 至 2024-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10456888
• 关键词: Adopted; Animals; Antibiotics; Binding; Biochemical; Biological; Biological Assay; Biology; Cells; Chemistry; Communication; Community Developments; Complex; Cryoelectron Microscopy; Development; Drug Targeting; Enzymes; Genetic; Genomics; Genus Mycobacterium; Goals; Knowledge; Macromolecular Complexes; Mediating; Membrane; Membrane Proteins; Membrane Transport Proteins; Metabolic; Multienzyme Complexes; Mycobacterium tuberculosis; Mycobacterium tuberculosis complex; National Institute of Allergy and Infectious Disease; Organism; Proteins; Research; Resources; Ribosomes; Role; Siderophores; Specificity; Structure; Supervision; Translations; Virulence; Work; base; chemical genetics; drug development; drug discovery; flexibility; genetic information; improved; inhibitor; innovative technologies; interdisciplinary approach; mycobacterial; new therapeutic target; novel; preclinical development; programs; protein structure; small molecule; small molecule inhibitor; structural biology; structural genomics; tuberculosis drugs

Project Summary – Overall The TB Structural Genomics Consortium (TBSGC) is a collaborative research group that has studied TB’s causative organism, Mycobacterium tuberculosis (Mtb), for the past 15 years. Over the years we have focused our goals to concentrate on proteins that are drug targets for novel antibiotics, and proteins whose structure might contribute to our knowledge of vulnerabilities in Mtb. We also supplemented our structural work with both chemistry and genetics to validate our targets, to obtain and optimize protein inhibitors, and to determine their underlying biological roles within Mtb. Our multidisciplinary approach has allowed us to add considerable knowledge to mycobacterial structures, and to leverage this information to inform drug development. Significantly, results of the last TBSGC cycle has led to a novel anti-TB drug that is in late pre- clinical development along with others compounds that have been adopted by anti-TB drug developers. In this TBSGC renewal, we propose to incorporate new innovative technologies, including membrane protein structures and cryo-EM, to strengthen our commitment to TB drug development. We will leverage structure determination to both understand function and identify potential small molecule inhibitors. The fundamental goal of this project is to accelerate TB drug discovery by understanding essential functions of the mycobacterial cell and providing validated targets and inhibitors to our partners in the TB drug development community.

项目摘要--总体 结核病结构基因组学联盟(TBSGC)是一个合作研究组织，它拥有 在过去的15年里，研究了结核病的病原体--结核分枝杆菌(Mtb)。完毕 多年来，我们一直将目标集中在作为新药靶点的蛋白质上 抗生素和蛋白质，它们的结构可能有助于我们了解 山地车。我们还用化学和遗传学补充了我们的结构工作，以验证我们的 靶点，以获得和优化蛋白质抑制剂，并确定其潜在的生物学作用 在MTB内。我们的多学科方法使我们能够增加大量的知识 分枝杆菌结构，并利用这些信息来为药物开发提供信息。 值得注意的是，上一次TBSGC周期的结果导致了一种新的抗结核病药物，该药物处于晚期 抗结核药物采用的其他化合物的临床进展 开发商。 在此次TBSGC续期中，我们建议采用新的创新技术，包括 膜蛋白结构和冷冻-EM，以加强我们对结核病药物的承诺 发展。我们将利用结构决定来理解功能和确定 潜在的小分子抑制剂。这个项目的基本目标是加速治疗结核病的药物 通过了解分枝杆菌细胞的基本功能并提供经过验证的 向我们在结核病药物开发界的合作伙伴提供靶标和抑制剂。

项目成果

Advances In Mycobacterium Tuberculosis Therapeutics Discovery Utlizing Structural Biology.

利用结构生物学发现结核分枝杆菌治疗的进展。

• 发表时间: 2012
• 期刊: Infectious disorders drug targets
• 作者: Chim,Nicholas;Owens,CedricP;Contreras,Heidi;Goulding,CeliaW
• 通讯作者: Goulding,CeliaW

Structural and biochemical analyses of Mycobacterium tuberculosis N-acetylmuramyl-L-alanine amidase Rv3717 point to a role in peptidoglycan fragment recycling.

结核分枝杆菌 N-乙酰胞壁酰-L-丙氨酸酰胺酶 Rv3717 的结构和生化分析表明其在肽聚糖片段回收中发挥作用。

• DOI: 10.1074/jbc.m113.510792
• 发表时间: 2013
• 期刊: The Journal of biological chemistry
• 作者: Prigozhin,DaniilM;Mavrici,Daniela;Huizar,JohnP;Vansell,HilaryJ;Alber,Tom
• 通讯作者: Alber,Tom

Covalent Inactivation of Mycobacterium tuberculosis Isocitrate Lyase by cis-2,3-Epoxy-Succinic Acid.

顺式 2,3-环氧琥珀酸共价灭活结核分枝杆菌异柠檬酸裂解酶。

• DOI: 10.1021/acschembio.0c00740
• 发表时间: 2021
• 期刊: ACS chemical biology
• 影响因子: 4
• 作者: Pham,TrucViet;Mellott,DrakeM;Moghadamchargari,Zahra;Chen,Kevin;Krieger,Inna;Laganowsky,Arthur;Sacchettini,JamesC;Meek,ThomasD
• 通讯作者: Meek,ThomasD

Optimization of TAM16, a Benzofuran That Inhibits the Thioesterase Activity of Pks13; Evaluation toward a Preclinical Candidate for a Novel Antituberculosis Clinical Target.

• DOI: 10.1021/acs.jmedchem.1c01586
• 发表时间: 2022-01-13
• 期刊: Journal of medicinal chemistry
• 影响因子: 7.3
• 作者: Wilson C;Ray P;Zuccotto F;Hernandez J;Aggarwal A;Mackenzie C;Caldwell N;Taylor M;Huggett M;Mathieson M;Murugesan D;Smith A;Davis S;Cocco M;Parai MK;Acharya A;Tamaki F;Scullion P;Epemolu O;Riley J;Stojanovski L;Lopez-Román EM;Torres-Gómez PA;Toledo AM;Guijarro-Lopez L;Camino I;Engelhart CA;Schnappinger D;Massoudi LM;Lenaerts A;Robertson GT;Walpole C;Matthews D;Floyd D;Sacchettini JC;Read KD;Encinas L;Bates RH;Green SR;Wyatt PG
• 通讯作者: Wyatt PG

Mycobacterial recombineering.

• DOI: 10.1007/978-1-4939-2450-9_10
• 发表时间: 2015-01-01
• 期刊: Methods in molecular biology (Clifton, N.J.)
• 作者: Murphy, Kenan C;Papavinasasundaram, Kadamba;Sassetti, Christopher M
• 通讯作者: Sassetti, Christopher M