Anaerobic shock as a novel treatment for tuberculosis

描述（由申请人提供） 翻译后摘要：结核病每年造成200万人死亡。多重耐药（MDR）感染的日益增加的患病率和广泛/完全耐药（XDR/CDR）结核杆菌的出现使得目前的化疗越来越不有效。该提案的长期目标是基于我们最近的观察，即厌氧休克引起结核分枝杆菌的快速和广泛的细胞溶解（例如，在5分钟内细菌存活率下降> 105），开发用于结核病的新疗法。将探讨两个大方向。一种是用厌氧气体治疗受感染宿主的肺部。最初，感染M.包括MDR和XDR临床分离株在内的所有结核分枝杆菌菌株将用于测试体外优化的厌氧气体混合物的有效性和安全性。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。我们在这方面的总体成就应该提供一种医疗程序，将在几小时甚至几分钟内实现痰菌阳转阴，而不是传统联合化疗所需的几周。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。遗传学、基因组学和生物化学方法将用于使用直接浊度和荧光测定来鉴定参与厌氧休克诱导的细胞溶解的相关基因和编码蛋白。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。从第二部分工作中获得的信息将用于设计分枝杆菌细胞裂解的小分子活化剂的高通量筛选。该项目的成功将彻底改变结核病治疗，并产生一种新的药物，无论其耐药性（MDR或XDR）或生理状态（生长或休眠），都将迅速治愈结核病。 公共卫生相关性：结核病感染了世界三分之一的人口，每年造成200万人死亡。日益严重的耐药性问题可能很快使目前所有可用的治疗方案无效。本项目旨在通过诱导结核分枝杆菌的自毁性自溶来开发一种新型、快速和高效的结核病治疗方法。

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.