Vulnerabilities in Metabolite, Heme-lron and Redox Environments

代谢物、血红素铁和氧化还原环境中的漏洞

• 批准号: 8353059
• 负责人: Celia Goulding
• 金额: $ 30.94万
• 依托单位: TEXAS A&M UNIVERSITY
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/8353059
• 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; Heme; Homeostasis; Human Development; Hydrolase; Immunology; Instruction; Knowledge; Lactamase; Ligands; Lipids; Methods; Microbiology; Molecular; Molecular Conformation; Multienzyme Complexes; Mycobacterium tuberculosis; Oxidation-Reduction; Pathway interactions; Peptides; Production; Proteins; Regulation; Regulatory Pathway; Research Personnel; Role; Signal Pathway; 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

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 pepfidoglycan (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 enzymatically (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 specificty. By testtng fundamental hypotheses about cell-wall biosynthettc pathways and regulatory networks, this project sets the stage to develop potent, selective inhibitors of Mtb growth.

该项目的重点是定义结核分枝杆菌（MTB）细胞壁的新机械范例。 生物合成和重塑，这对于细胞生长和分裂至关重要。细胞壁生物合成是众所周知的临界抗结核，包括异念珠菌，环丝氨酸和乙糖醇。我们将集中精力于细胞壁的脱氟糖（PG）层，该层是芽孢杆菌结构完整性的网络。最近的进展已经鉴定出参与PG稳态的蛋白质（PG水解酶）或调节作用（PKNB，FHAA和脂质II Flippase）。这些以及其他细胞壁生物合成酶代表了可能利用用于设计新结核药物的潜在脆弱性。 我们将通过我们的核心能力来解决有关MTB细胞壁生物发生及其调节的主要问题，采用多学科的多学科方法。在AIM 1中，我们将定义PG水解酶自动抑制的新分子机制，以发现其毒性是如何降低的。在AIM 2中，我们将在结构上表征活性PG水解酶的复合物。为了发现间接的细胞壁漏洞，我们 还将确定在不同环境中控制PG生物合成的调节因素复合物的结构。这些研究将首次控制PG完整性的激活机制。 AIM 3的重点是确定PG水解酶和其他细胞壁靶标的小分子复合物的结构，以定义亚率和抑制剂结合特定的基础。 通过对细胞壁生物合成途径和监管网络的测试基本假设，该项目为发展有效的，有选择性的MTB增长抑制剂奠定了基础。