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

结核分枝杆菌是人类和动物的主要病原体。人类疾病可以获得药物治疗，但需要六个月的时间，这在结核病最常见的发展中国家是不切实际的。随之而来的不遵守治疗制度导致出现抗药性。现在，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“极端抗药性”菌株。如果能缩短治疗周期，治疗将会有效得多。治疗方案必须延长的主要原因是皮损中的一小部分细胞对抗生素相对耐受，这种现象被称为表型耐受或非遗传性抗生素耐药。表型耐受的机制目前尚不清楚，但我们最近发现，它与结核分枝杆菌生长缓慢有关。我们最近通过理论研究表明，单个细菌细胞生长速度的随机变化可能是产生持久体的机制。这个项目是在一个实验系统中研究这一假说。这一结果将提供对表型耐受机制的新理解，这可能为干扰耐药机制提供新的靶点和机会，从而提高结核病治疗的有效性。

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.