Treatment and Control of Mycobacterial Infections

分枝杆菌感染的治疗和控制

• 批准号: 7011189
• 负责人: JOHN-PAUL J YU
• 金额: $ 2.35万
• 依托单位: UNIVERSITY OF ILLINOIS AT URBANA-CHAMPAIGN
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-12-31 至 2009-12-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7011189
• 关键词: HIV infections; Mycobacterium tuberculosis; adenosine triphosphate; antiinfective agents; bacteria infection mechanism; biosynthesis; cytotoxicity; drug resistance; enzyme activity; intravenous drug abuse; isoniazid; microorganism disease chemotherapy; predoctoral investigator; rifamycins; tuberculosis

DESCRIPTION (provided by applicant): Despite the recent downward trend in drug use, the prevalence of injection drug abuse is still higher than in the early 1990s. The health and social consequences of drug abuse - HIV/AIDS, tuberculosis, violence, and crime - have a devastating impact on society and cost billions of dollars each year. Injection drug abuse is particularly remarkable in that abusers face unique secondary consequences of their addictions, such as HIV/AIDS and tuberculosis, which are both potential complicating factors in their overall treatment. Among injection drug users with HIV/AIDS, the grampositive bacterium Mycobacterium tuberculosis is the principle causative agent of TB infections seen. Treatment for TB infections against Mycobacterium tuberculosis in these populations involves the administration of the antibiotics rifampicin and isoniazid but emerging multidrug-resistant (MDR) TB strains have seriously compromised and complicated treatment. To explore alternative methodologies for the treatment and control of TB infections we propose to study the antimicrobial peptide nisin. Over the last 50 years, nisin has demonstrated an undiminished selective cytotoxicity towards gram-positive bacteria. Recent in vitro studies have shown that nisin exhibits antimycobacterial activities by depleting ATP and the proton motive force in mycobacteria and also by causing the loss of the permeability barrier of the cytoplasmic membrane. The goal of the studies described herein is to understand the biosynthesis of nisin by investigating the enzymes responsible for its synthesis and to explore the hypothesis that modifications to these enzymes can generate novel enzymes capable of generating new antibiotics based on the nisin framework that display greater antimycobactericidal activity.

描述（由申请人提供）：尽管药物使用的近期下降趋势，但注射药物滥用的患病率仍然高于1990年代初期。药物滥用的健康和社会后果 - 艾滋病毒/艾滋病，结核病，暴力和犯罪 - 每年对社会和成本数十亿美元产生毁灭性影响。注射药物滥用尤其显着，因为施虐者面临其成瘾的独特次要后果，例如艾滋病毒/艾滋病和结核病，这都是他们整体治疗中潜在的复杂因素。在注射吸毒者中，患有艾滋病毒/艾滋病的药物，结核分枝杆菌的息肉细菌是看到的结核病感染的主要诱因。在这些人群中针对结核分枝杆菌的结核病感染的治疗涉及抗生素利福平和异念珠菌的给药，但新兴的耐多药（MDR）结核病菌株严重损害了且复杂的治疗。为了探索用于治疗和控制结核病感染的替代方法，我们建议研究抗菌肽尼日蛋白。在过去的50年中，Nisin对革兰氏阳性细菌的选择性细胞毒性不足。最近的体外研究表明，Nisin通过耗尽ATP和分枝杆菌中的质子动力表现出抗菌活性，并通过导致细胞质膜的渗透性屏障的丧失而表现出抗菌活性。本文所述的研究的目的是通过研究负责其合成的酶来了解尼肽的生物合成，并探讨以下假设：对这些酶的修饰可以产生能够基于具有更大抗微生物抗细胞固醇活性的Nisin框架产生新抗生素的新型酶。