Riboswitch-controlled glycine metabolism in pathogenic mycobacteria.

分枝杆菌疾病，如结核病、麻风病、布鲁里溃疡，每年影响数百万人。虽然这些疾病有治疗方法，但抗生素耐药性正在上升，并构成一种重要的治疗方法。此外，其他新出现的分枝杆菌感染，如由脓肿分枝杆菌、大分枝杆菌和豪斯顿分枝杆菌引起的软组织和肺部感染，自然是多重耐药的，因此是重要的新的医学挑战。我们和其他人已经证明了细菌新陈代谢的重要性，特别是在结核病的背景下，氨基酸新陈代谢。我们现在想了解甘氨酸代谢是如何促进感染的，甘氨酸代谢是分枝杆菌生理学中一个重要的未被研究的角落。氨基酸甘氨酸不仅对蛋白质合成是必不可少的，而且它的代谢通过单碳库直接与中枢和核苷酸代谢联系在一起。此外，虽然人类细胞对高浓度甘氨酸具有高度耐受性，但细菌，包括分枝杆菌，对甘氨酸毒性明显更敏感。与我们以前的工作形成鲜明对比的是，我们不仅将研究甘氨酸代谢和解毒，还将研究其他致病分枝杆菌。具体地说，我们将研究：(I)甘氨酸代谢的分子决定因素(酶和甘氨酸核糖开关)和负责基因表达控制的确切调控机制；(Ii)新陈代谢和生理如何在细菌水平上应对甘氨酸的毒性水平的挑战，以及这如何与抗生素治疗协同作用，以及(Iii)在实验感染期间削弱分枝杆菌甘氨酸代谢/解毒的效果。从长远来看，我们将阐明建立完全毒力所需的基本代谢系统，这可能是抗感染药物发现和开发的一个有吸引力的领域。

Mycobacterial disease such as tuberculosis, leprosy, Buruli ulcer affect millions of people every year. While there are treatments for these diseases, antibiotic resistance is on the rise and poses a significant treat. Additionally, other emerging mycobacterial infections, such as soft tissue and lung infections caused by M. abscessus, M. mageritense and M. houstonense, are naturally multi-drug resistant, and therefore represent important novel medical challenges. We and others have demonstrated the importance of bacterial metabolism, and particularly, amino acid metabolism, in the context of tuberculosis. We now want to understand how glycine metabolism, a significantly under investigated corner of mycobacterial physiology, promotes infection. The amino acid glycine is not only essential for protein synthesis, but its metabolism is directly linked to central and nucleotide metabolism, via the one-carbon pool. Additionally, while human cells are highly tolerant to high concentrations of glycine, bacteria, including mycobacteria, are significantly more sensitive to glycine toxicity. In sharp contrast to our previous work, we will study glycine metabolism and detoxification not only with Mycobacterium tuberculosis, but also on other pathogenic mycobacteria. By doing that, we intend to identify and characterise more general aspects of mycobacterial physiology relevant to different mycobacterial infections.Specifically, we will study:(i) the molecular determinants of glycine metabolism (enzymes and a glycine riboswitch) and the exact regulatory mechanism responsible to gene expression control, (ii) how metabolism and physiology respond to challenge with otherwise toxic levels of glycine at the bacterial level, and how this synergises with antibiotic treatment and (iii) the effect of crippling mycobacterial glycine metabolism/detoxification during experimental infection. In the longer term, we will elucidate fundamental metabolic systems required for the establishment of full virulence, which might represent an attractive area for anti-infective drug discovery and development.