Vulnerabilities in Mycobacterial Cell-Wall Biogenesis

分枝杆菌细胞壁生物发生中的脆弱性

• 批准号: 8353014
• 负责人: THOMAS C ALBER
• 金额: $ 41.02万
• 依托单位: TEXAS A&M UNIVERSITY
• 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 2016-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8353014
• 关键词: Address; Alanine; Amidohydrolases; Anabolism; Antibiotic Resistance; Antibiotics; Autolysis; Bacillus (bacterium); Binding; Biochemistry; Biogenesis; Carbapenems; Carboxypeptidase; Cell Wall; Cell division; Cells; Collaborations; Complex; Cues; Cycloserine; Drug Delivery Systems; Environment; Enzymes; Ethambutol; Genetic; Genetic Structures; Genus Mycobacterium; Growth; Health; Homeostasis; Human Development; Hydrolase; Immunology; Instruction; Knowledge; Lactamase; Ligands; Lipids; Methods; Microbiology; Molecular; Molecular Conformation; Multienzyme Complexes; Mycobacterium tuberculosis; N-Acetylmuramoyl-L-alanine Amidase; Pathway interactions; Peptides; Peptidoglycan; Production; Proteins; Regulation; Regulatory Pathway; Research Personnel; Role; Signal Pathway; Specificity; Staging; Structure; Substrate Specificity; Sulfur; Testing; Time; Toxic effect; Work; amidase; analog; base; cell envelope; cell growth; chemical genetics; design; inhibitor/antagonist; innovation; isoniazid; killings; member; multidisciplinary; mycobacterial; novel; novel therapeutics; programs; protein protein interaction; small molecule; sugar; tuberculosis drugs

I PROJECT SUMMARY (See instructions): This project is focused on defining new mechanistic paradigms for Mycobacterium tuberculosis (Mtb) cell wall. biosynthesis and remodeling, which are essential for cell growth and division. Cell-wall biosynthesis is the target of well-known, critical anti-tuberculars, including isoniazid, cycloserine and ethambutol. We will concentrate on the peptidoglycan (PG) layer of the cell wall, which serves as a meshwork for the structural integrity of the bacillus. Recent progress has identified proteins involved in PG homeostasis either enzymaticaily (PG hydrolases) or in regulatory roles (PknB, FhaA, and the lipid II flippase). These, along with other cell-wall biosynthetic enzymes, represent potential vulnerabilities that could be exploited for design of new TB drugs. We will take a multidisciplinary, multi-investigator approach enabled by our Core capabilities to address major questions about Mtb cell-wall biogenesis and its regulation. In Aim 1, we will define new molecular mechanisms of auto-inhibition of PG hydrolases to discover how their toxicity is mitigated. In Aim 2, we will structurally characterize complexes of active PG hydrolases. To uncover indirect cell-wall vulnerabilities, we also will determine the structures of complexes of regulatory factors that control PG biosynthesis in diverse environments. These studies will uncover for the first time activation mechanisms that control PG integrity. Aim 3 focuses on determining structures of small-molecule complexes of PG hydrolases and other cell-wall targets to define the basis for subrate- and inhibitor-binding specificity. By testing fundamental hypotheses about cell-wall biosynthettc pathways and regulatory networks, this project sets the stage to develop potent, selective inhibitors of Mtb growth.

I项目总结（见说明）： 该项目的重点是定义结核分枝杆菌（Mtb）细胞壁的新机制范例。生物合成和重塑是细胞生长和分裂所必需的。细胞壁生物合成是众所周知的关键抗结核药的靶点，包括异烟肼、环丝氨酸和乙胺丁醇。我们将集中在细胞壁的肽聚糖（PG）层，它作为芽孢杆菌结构完整性的网络。最近的进展已经确定了参与PG稳态的蛋白质，无论是酶促作用（PG水解酶）还是调节作用（PknB，FhaA和脂质II翻转酶）。这些酶，沿着其他细胞壁生物合成酶，代表了潜在的脆弱性，可用于设计新的结核病药物。我们将采取多学科，多研究者的方法，通过我们的核心能力，以解决有关结核分枝杆菌细胞壁生物合成及其调控的主要问题。在目标1中，我们将定义PG水解酶的自抑制的新分子机制，以发现它们的毒性如何减轻。在目标2中，我们将从结构上表征活性PG水解酶的复合物。为了揭示间接的细胞壁脆弱性，我们还将确定在不同环境中控制PG生物合成的调节因子复合物的结构。这些研究将首次揭示控制PG完整性的激活机制。目标3的重点是确定PG水解酶和其他细胞壁靶点的小分子复合物的结构，以定义底物和抑制剂结合特异性的基础。通过测试关于细胞壁生物合成途径和调控网络的基本假设，该项目为开发有效的选择性结核分枝杆菌生长抑制剂奠定了基础。