Anaerobic shock as a novel treatment for tuberculosis

无氧休克作为结核病的新型治疗方法

• 批准号: 7981664
• 负责人: Xilin Zhao
• 金额: $ 111.38万
• 依托单位: UNIV OF MED/DENT OF NJ-NJ MEDICAL SCHOOL
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-09-30 至 2013-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7981664
• 关键词: Achievement; Autolysis; Bacillus (bacterium); Biochemical; Biological Assay; Cells; Clinical; Clinical Trials; Combination Drug Therapy; Cyclic Peptides; Cytolysis; Drops; Drug resistance; Fluorescence; Funding; Gases; Genes; Genetic; Genomics; Goals; Hour; In Vitro; Infection; Lung; Mediating; Medical; Molecular; Multi-Drug Resistance; Mycobacterium tuberculosis; Oryctolagus cuniculus; Peptide Library; Pharmaceutical Preparations; Physiological; Prevalence; Procedures; Proteins; Resistance profile; Safety; Shock; Sputum; Tuberculosis; Work; abstracting; base; chemotherapy; design; efficacy testing; high throughput screening; in vivo; killings; mycobacterial; novel; small molecule; success; tuberculosis treatment

DESCRIPTION (Provided by the applicant) Abstract: Tuberculosis kills 2 million people every year. The increasing prevalence of multiple drug- resistant (MDR) infections and the emergence of extensively/completely drug-resistant (XDR/CDR) tubercle bacilli are making currently chemotherapies less and less effective. The long-term goal of this proposal is to develop a novel therapy for tuberculosis based on our recent observation that anaerobic shock causes rapid and extensive cell lysis of Mycobacterium tuberculosis (e.g. > 105 drop in bacterial survival within 5 min). Two general directions will be explored. One is treatment of lungs of infected hosts with anaerobic gas. Initially, rabbits infected with M. tuberculosis, including MDR and XDR clinical isolates, will be used to test the efficacy and safety of anaerobic gas mixtures optimized in vitro. Clinical trials, for which additional funding will be sought, will be designed based on our rabbit work. Our overall achievement of this line of work should provide a medical procedure that will achieve a positive to negative sputum bacilli conversion in hours, or perhaps even minutes, rather than the weeks required for traditional combination chemotherapy. The second direction focuses on the molecular mechanisms underlying anaerobic shock-mediated rapid cell lysis. Genetic, genomic, and biochemical approaches will be used to identify relevant genes and the encoded proteins involved in anaerobic shock-induced cell lysis using straight-forward turbidity and fluorescence assays. An in vivo cyclic peptide library will also be constructed and screened for autolysis- inducing activities similar to that conferred by anaerobic shock. Information gained from this second part of the work will be used to design high throughput screens for small-molecule activators of mycobacterial cell lysis. The success of this project will revolutionize tuberculosis therapy and generate a novel drug that would rapidly cure tuberculosis regardless of its drug- resistance profile (MDR or XDR) or physiological status (growing or dormant). Public Health Relevance: Tuberculosis infects a third of the world's population and kills 2 million people a year. The increasing problem of drug resistance may soon make all currently available treatment options ineffective. The present program seeks to develop a novel, rapid, and highly efficient treatment of tuberculosis upon induction of self-destructive autolysis of Mycobacterium tuberculosis.

描述（申请人提供） 摘要：每年结核病会杀死200万人。多种抗药性（MDR）感染的患病率增加，并且广泛/完全耐药（XDR/CDR）结节杆菌的出现正在使目前化学疗法越来越降低。该提案的长期目标是根据我们最近的观察结果开发一种新的结核病疗法，即厌氧休克会导致结核分枝杆菌的快速而广泛的细胞裂解（例如，在5分钟内细菌存活率下降105）。将探索两个一般方向。一种是用厌氧气体的感染宿主的肺处理。最初，感染结核分枝杆菌的兔子（包括MDR和XDR临床分离株）将用于测试在体外优化的厌氧气体混合物的功效和安全性。将根据我们的兔子工作设计额外资金的临床试验。我们对这项工作的总体成就应提供一种医疗程序，该程序将在数小时甚至几分钟内获得阳性至负细菌转化的阳性，而不是传统组合化学疗法所需的几周。第二个方向着重于厌氧休克介导的快速细胞裂解的分子机制。遗传，基因组和生化方法将用于鉴定相关的基因以及使用直发浊度和荧光测定法的厌氧休克诱导的细胞裂解所涉及的编码蛋白。还将构建并筛选一个体内环状肽库，以进行自溶的诱导活动，类似于厌氧休克所赋予的活动。从第二部分获得的信息将用于设计分枝杆菌细胞裂解的小分子激活剂的高吞吐量筛选。该项目的成功将彻底改变结核病疗法，并产生一种新型药物，该药物将迅速治愈结核病，而不管其耐药性概况（MDR或XDR）或生理状况（生长或休眠）。 公共卫生相关性：结核病感染了世界人口的三分之一，每年造成200万人丧生。耐药性越来越大的问题可能很快使所有当前可用的治疗选择无效。本计划旨在通过诱导结核分枝杆菌的自我毁灭性自动解诱导结核病来开发新型，快速且高效的结核病治疗。