3-Ketoacyl ACP Synthase III: A Novel Antibiotic Target

3-酮脂酰 ACP 合酶 III：新型抗生素靶点

• 批准号: 7095655
• 负责人: KEVIN A REYNOLDS
• 金额: $ 20.71万
• 依托单位: PORTLAND STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-08-01 至 2008-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7095655
• 关键词: X ray crystallography; acetyl coA; active sites; acyl carrier protein; antibacterial agents; antibiotics; antiinfective agents; antimalarial agents; catalyst; chemical binding; drug design /synthesis /production; drug interactions; drug screening /evaluation; enzyme inhibitors; enzyme structure; enzyme substrate; fatty acid biosynthesis; fatty acid synthase; fluorimetry; nuclear magnetic resonance spectroscopy; polymerase chain reaction; site directed mutagenesis; stop flow technique

DESCRIPTION (provided by applicant): Fatty acid biosynthesis by a type II dissociated fatty acid synthase (FAS) is a fundamental and indispensable metabolic pathway in many organisms, including bacteria and parasites. The distinctions between this and the multifunctional type I FAS of higher organisms offer a selective target for the design of novel antibacterial and antiparasitic agents, needed to combat the resurgence of antibiotic-resistant bacteria and multidrug-resistant forms of the malaria-causing plasmodial parasites. In all type II FAS systems, the initial condensation step is carried out by 3-ketoacyl acyl carrier protein (ACP) synthase III (KASIII, FabH), which catalyzes the condensation of an acyl CoA substrate with malonyl ACP to generate a 3-ketoacyl ACP product. FabH also appears to play a key role in regulation of fatty acid biosynthesis and is not targeted by any current drugs, making it a particularly attractive new target for drug design. The long-term objective of our work is to understand the structural and mechanistic bases of FabH that define its physiological roles and to use this information to generate novel potent and selective inhibitors. This grant will extend our study of FabH enzymes from organisms such as Escherichia coil and Staphylococcus aureus, which initiate de novo fatty acid biosynthesis from different short chain acyl CoA substrates, and Mycobacterium tuberculosis, which uses FabH to initiate mycolate biosynthesis from long chain acyl CoA substrates. Mutational analyses and crystallography will be used to investigate the differing substrate and inhibitor specificities of these enzymes. In conjunction with ongoing crystallographic, molecular modeling and kinetic analyses, the mode of binding of 1,2-dithiole-3-one and related compounds which are potent novel active site FabH inhibitors, and a second series of inhibitors that appear to bind in the FabH phosphopantetheine binding channel, will be investigated. The information gathered from these studies will be used to design, synthesize and ultimately test inhibitors, which maximize interactions with both active site residues and those in either the acyl-binding pocket or phosphopantetheine-binding channel. Such compounds should have enhanced activity and selectivity against FabH and be powerful new lead compounds for development of novel antibacterial and antiparastitic/antimalarial drugs.

描述（由申请人提供）：II型解离脂肪酸合成酶（FAS）的脂肪酸生物合成是许多生物，包括细菌和寄生虫的基本和不可或缺的代谢途径。这与高等生物的多功能I型FAS之间的区别为设计新型抗菌和抗寄生虫剂提供了一个选择性靶标，这是对抗抗生素耐药细菌和引起疟疾的多重耐药疟原虫的复苏所必需的。在所有II型FAS体系中，初始缩合步骤由3-酮酰基酰基载体蛋白（ACP）合成酶III （KASIII, FabH）进行，它催化酰基辅酶a底物与丙二醇基ACP缩合，生成3-酮酰基ACP产物。FabH似乎在脂肪酸生物合成的调节中也起着关键作用，目前还没有任何药物针对它，这使它成为药物设计的一个特别有吸引力的新靶点。