Investigation of stochastic variations in growth rate as the mechanism of drug tolerance in Mycobacterium tuberculosis

结核分枝杆菌是人和动物的主要病原体。药物治疗可用于人类疾病，但需要六个月，这在结核病最常见的发展中国家是不切实际的。对治疗方案的不遵守导致抗药性的出现。这是一个世界性的大问题，包括英国在内的许多国家都出现了几乎无法治愈的“极端耐药”菌株。如果治疗制度能够缩短，治疗将更加有效。治疗方案必须如此延长的主要原因是病变中的细胞亚群对抗生素具有相对耐受性，这种现象称为表型耐受性或非遗传性抗生素抗性。表型耐受的机制目前尚不清楚，但我们最近发现它与M.结核我们最近通过理论研究表明，单个细菌细胞中生长速率的随机变化可能是产生持久菌的机制。本项目将在一个实验系统中研究这一假设。这些结果将提供对表型耐受性的机制基础的新理解，这可能提供新的靶点和机会来干扰耐药机制，从而提高TB治疗的功效。

Mycobacterium tuberculosis is a major pathogen of man and animals. Drug treatment is available for human disease but it takes six months, which is impractical in developing world settings where TB is most common. Consequent non-compliance with treatment regimes leads to the emergence of drug-resistance. This is now a major world-wide problem with practically incurable 'extreme drug-resistant' strains appearing in many countries, including the UK. Treatment would be much more effective if treatment regimes could be shortened. The principle reason why treatment regimes have to be so prolonged is that that a sub-population of cells in lesions are relatively tolerant to the antibiotic, a phenomenon termed phenotypic tolerance or non-inherited antibiotic resistance. The mechanism of phenotypic tolerance is currently unknown but we have recently discovered that it is associated with slow growth in M. tuberculosis. We have recently shown, through theoretical studies, that random variations of growth rate in individual bacteria cells may the mechanisms for generating persisters. This project is to investigate this hypothesis in an experimental system. The results will provide a new understanding of the mechanistic basis of phenotypic tolerance that is likely to provide new targets and opportunities to interfere with the resistance mechanisms and thereby increase efficacy of TB treatment.