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（由申请人提供） 摘要：结核病每年夺去200万人的生命。多重耐药（MDR）感染的日益流行以及广泛/完全耐药（XDR/CDR）结核杆菌的出现使得目前的化疗效果越来越差。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细胞快速而广泛的裂解（例如，5分钟内细菌存活率下降> 105）。将探索两个总体方向。一是用厌氧气体治疗感染宿主的肺部。最初，感染结核分枝杆菌（包括MDR和XDR临床分离株）的兔子将用于测试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临床试验，为此将寻求额外的资金。我们在这方面工作的总体成就应该提供一种医疗程序，能够在数小时甚至数分钟内实现痰杆菌从阳性到阴性的转变，而不是传统联合化疗所需的数周。第二个方向侧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通过直接的浊度和荧光测定来鉴定参与厌氧休克诱导的细胞裂解的相关基因和编码蛋白质。还将构建体内环肽文库并筛选类似于厌氧休克所赋予的自溶诱导活性。从工作的第二部分获得的信息将用于设计分枝杆菌细胞裂解小分子激活剂的高通量筛选。该项目的成功将彻底改变结核病治疗方法，并产生一种能够快速治愈结核病的新药，无论其耐药情况（MDR 或 XDR）或生理状态（生长或休眠）如何。 公共卫生相关性：结核病感染了世界三分之一的人口，每年导致 200 万人死亡。日益严重的耐药性问题可能很快就会使目前所有可用的治疗方案失效。本项目旨在开发一种新型、快速、高效的结核病治疗方法，通过诱导结核分枝杆菌的自我破坏性自溶来治疗结核病。