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Viable but Nonculturable Mtb

可行但不可培养的山地车

基本信息

批准号：
10057813
负责人：
Michael Stephen Glickman
金额：
$ 94.76万
依托单位：
WEILL MEDICAL COLL OF CORNELL UNIV
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-07-01 至 2021-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10057813
关键词：
Address Agar Animal Model Antioxidants Bacterial Infections Biological Assay Chemicals Clinical Clinical Trials Collaborations Colony-Forming Units Assay Colony-forming units Complement Detection Drug Tolerance Drug resistance in tuberculosis Enzymes Essential Genes Exposure to Extinction (Psychology)Fumarates Funding Future Genes Genetic Genomic DNA Genomics HIV Seronegativity Human Human Resources Hypoxia In Vitro Knowledge Left Leprosy Liquid substance M. tuberculosis genome Metabolic Metabolic Pathway Methods Molecular Target Mus Mycobacterium tuberculosis NBL1 gene Oxidants Pathway interactions Patients Pharmaceutical Preparations Phenotype Physiological Population Predisposition Preparation Pyruvate Quantitative Reverse Transcriptase PCR Regulon Relapse Reporting Reproducibility Research Resuscitation Rifampin Specimen Sputum Starvation Stress Supervision Technology Testing Tissues Training Transcript Tuberculosis Variant Work axenic culture bactericide base catalase chemotherapy clinically significant deep sequencing drug candidate drug testing improved in vivo evaluation inhibitor/antagonist knock-down mouse model pre-clinical response standard care standard of care transcriptome treatment duration tuberculosis drugs tuberculosis treatment

项目摘要

Tuberculosis (TB) takes longer to cure than almost any other bacterial infection. Subpopulations of Mycobacterium tuberculosis (Mtb) become phenotypically drug-tolerant in association with host-imposed stresses that put Mtb into a slowly-replicating or non-replicating state (here called NR for simplicity). We hypothesize that NR Mtb represent a major population of the "persisters" that survive the first months of chemotherapy. One subset of NR Mtb is termed "viable but nonculturable" (VBNC) because they elude detection as colony forming units (CFU) on agar. The nonculturability of VBNC Mtb has left us with almost no knowledge of their essential genes, metabolic pathways or susceptibilities to specific drugs and drug candidates. We have now improved a limiting dilution assay for VBNC Mtb and used it to confirm that an average of 87% of the viable Mtb detected in sputum from 33% of the untreated TB patients studied were VBNC forms missed both by CFU assays and by liquid culture in the BACTEC MGIT assay. Further, we developed a reproducible way to generate VBNC Mtb in vitro by prolonged starvation in axenic culture. In close collaboration with Project 5 and the Clinical Core, we will further improve and apply the resuscitation assay to characterize VBNC Mtb by chemical genomics in vitro, by genetics in the mouse, and by their presence in sputum from patients before and after standard therapy. We will deliver: compounds that eradicate VBNC Mtb in vitro and identification of the targets of these compounds; a mouse model where the efficacy of such inhibitors can be tested in vivo; and an assay that can be used in future clinical trials to complement the standard early bactericidal activity test on sputum so as to identify drugs that impact VBNC Mtb in the human host.

结核病比几乎任何其他细菌感染都需要更长的时间才能治愈。亚种群的