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: 8724066
• 负责人: Celia Goulding
• 金额: $ 6.07万
• 依托单位: UNIVERSITY OF CALIFORNIA-IRVINE
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-09-01 至 2013-09-02
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8724066
• 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 Targeting; 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）细胞壁的新机制范式。