Targets for short-course TB therapy

短期结核病治疗的目标

• 批准号: 7406004
• 负责人: CHRISTOPHER M SASSETTI
• 金额: $ 23.91万
• 依托单位: UNIV OF MASSACHUSETTS MED SCH WORCESTER
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-04-15 至 2010-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7406004
• 关键词: Accounting; Adopted; Adult; Agar; Animal Model; Animals; Antibiotic Resistance; Antibiotic Therapy; Antibiotics; Bacteria; Bacterial Genes; Candidate Disease Gene; Cause of Death; Cell Death; Cells; Cessation of life; Chemicals; Clinical; Communicable Diseases; Condition; Disease; Drug Delivery Systems; Drug resistance; Environment; Epidemic; Essential Genes; Fibrinogen; Future; Genes; Genetic; Growth; Improve Access; In Vitro; Infection; Lead; Metabolic; Methodology; Methods; Molecular; Multi-Drug Resistance; Mycobacterium tuberculosis; Numbers; Organism; Pathway interactions; Pharmaceutical Preparations; Prevalence; Rate; Recurrent disease; Regulation; Scourge; Sterilization for infection control; System; Testing; Therapeutic; Time; Treatment Failure; Treatment Protocols; Tuberculosis; Work; chemotherapy; design; gene function; improved; in vivo; inhibitor/antagonist; insight; killings; mutant; mycobacterial; novel; novel strategies; pandemic disease; pathogen; prevent; transposon site hybridization; tuberculosis treatment

DESCRIPTION (provided by applicant): Despite the availability of several effective antibiotics, tuberculosis (TB) remains one of the leading causes of death due to infectious disease. The treatment of Mycobacterium tuberculosis infections is difficult largely due to this organism's remarkable ability to persist in spite of months or years of antibiotic treatment, often resulting in incomplete sterilization and recurrent disease. The inevitable consequence of inadequate therapy is the emergence of multidrug-resistant strains, which are even more challenging to treat. While clinical importance of this phenomenon cannot be overstated, a mechanistic understanding of bacterial persistence during therapy and strategies to treat this infection more effectively has proven elusive. We propose to employ two new genetic methodologies to understand antibiotic persistence at the molecular level, and to identify bacterial pathways that represent targets for a more effective therapeutics. First, we will employ "transposon-site hybridization" to identify mycobacterial genes that are required for persistence during antibiotic treatment of infected animals. This information will be used to characterize the antibiotic "tolerant" state adopted by this bacterium during infection and to define novel targets for synergistic therapies. As a parallel approach, we will develop a facile system for conditionally inhibiting essential genes of M. tuberculosis in order to define pathways whose inhibition results in rapid cell death under conditions similar to the in vivo environment. We expect both of these approaches to provide insight into the metabolic state of the bacterium that is responsible for its remarkable antibiotic tolerance during infection, and to identify potential targets for drugs that could reduce the time required to treat TB. Short-course therapy could have a dramatic effect on the current TB pandemic by improving access to effective treatment, reducing the prevalence of TB, and preventing the rapid emergence of drug resistance. Tuberculosis remains a scourge largely because currently available antibiotics are effective only after many months of administration. We will pursue two independent approaches to identify bacterial pathways that could be targeted by new drugs to shorten the duration of effective treatment. Short-course therapy could impact the worldwide tuberculosis epidemic both by making treatment more widely available and by reducing the rate at which drug-resistant strains emerge.

描述（由申请人提供）：尽管有几种有效的抗生素可供使用，但结核病（TB）仍然是传染病导致死亡的主要原因之一。结核分枝杆菌感染的治疗很困难，很大程度上是因为尽管经过数月或数年的抗生素治疗，这种生物体仍具有显着的持续存在能力，常常导致灭菌不完全和疾病复发。治疗不足的不可避免的后果是多重耐药菌株的出现，这使得治疗更具挑战性。虽然这种现象的临床重要性怎么强调都不为过，但事实证明，对治疗期间细菌持续存在的机制以及更有效地治疗这种感染的策略的理解是难以捉摸的。我们建议采用两种新的遗传方法来了解分子水平上的抗生素持久性，并确定代表更有效治疗靶标的细菌途径。首先，我们将采用“转座子位点杂交”来鉴定在感染动物的抗生素治疗期间持续存在所需的分枝杆菌基因。该信息将用于表征该细菌在感染期间采用的抗生素“耐受”状态，并确定协同治疗的新靶标。作为一种平行的方法，我们将开发一种简便的系统，用于有条件地抑制结核分枝杆菌的必需基因，以确定在类似于体内环境的条件下，其抑制导致细胞快速死亡的途径。我们期望这两种方法能够深入了解细菌的代谢状态，这种状态是其在感染期间具有显着抗生素耐受性的原因，并确定可以缩短治疗结核病所需时间的药物的潜在靶点。短期治疗可以通过改善获得有效治疗的机会、降低结核病的患病率并防止耐药性的迅速出现，对当前的结核病流行产生巨大影响。结核病仍然是一个祸害，很大程度上是因为目前可用的抗生素只有在施用数月后才有效。我们将采用两种独立的方法来确定新药可以针对的细菌途径，以缩短有效治疗的持续时间。短期治疗可以通过使治疗更广泛地提供并降低耐药菌株出现的速度来影响世界范围内的结核病流行。