DRUG TARGETING M. TUBERCULOSIS ARABINOSYL TRANSFERASES

针对结核分枝杆菌阿拉伯糖基转移酶的药物

• 批准号: 6372718
• 负责人: Richard E. Lee
• 金额: $ 10.8万
• 依托单位: UNIVERSITY OF TENNESSEE HEALTH SCI CTR
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-09-30 至 2003-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6372718
• 关键词: Mycobacterium tuberculosis; arabinose; bacterial genetics; bacterial proteins; cell wall; drug design /synthesis /production; ethambutol; microorganism culture; microorganism metabolism; pentosyltransferase; pharmacokinetics

DESCRIPTION (adapted from applicant's abstract): Tuberculosis is still a major cause of morbidity and mortality worldwide with the number of cases rising due to the HIV pandemic and the emergence of drug resistant strains. To combat these problems more effective antibiotics must be developed with better pharmacokinetics and lower toxicity than the drugs currently used. It is the aim of this proposal to study the chemistry, biochemistry and genomics of arabinose metabolism in M. tuberculosis and the effects of the front line drug ethambutol on the important mycoloylarabinogalactan (MAG) biosynthetic cascade. MAG is a unique lipidated polysaccharide surrounding and protecting the tubercular bacilli from the host immune system where it has found its evolutionary niche. The proteins involved in MAG biosynthesis are excellent drug targets because they are essential for growth of the organism and are unique to mycobacteria. However, a fundamental lack of knowledge of the genes involved prevents these targets from being developed. This proposal initiates the synthesis of advanced cell wall mimetic acceptors and the development of new arabinosyl transferase assays. Using these assays the relationship between the alpha (1-3) arabinosyl transferase activity and the frontline drug ethambutol will be defined. These assays will also allow detailed analysis of the mechanism of beta (1-2) arabinosyl transfer and aid in identification of the beta (1-2) transferase. The role of the protein encoded embCAB operon in arabinan biosynthesis will be explored, and its sensitivity to ethambutol and novel antimycobacterials examined. Most importantly the knowledge gained from these studies will initiate a thorough medicinal chemistry effort involving these targets for the development of new, more effective and less toxic treatments against tuberculosis.

描述（改编自申请人摘要）：结核病仍然是一个专业