Riboswitch-controlled glycine metabolism in pathogenic mycobacteria.

结核病、麻风病、布鲁里溃疡等分枝杆菌病每年影响数百万人。虽然有治疗这些疾病的方法，但抗生素耐药性正在上升，并提出了一个重要的治疗。M.P. mageritense和M. Houstonense是天然多药耐药性，因此代表了重要的新医学挑战。我们和其他人已经证明了细菌代谢的重要性，特别是在结核病的背景下，氨基酸代谢。我们现在想了解甘氨酸代谢是如何促进感染的，而甘氨酸代谢是分枝杆菌生理学中一个尚未充分研究的领域。氨基酸甘氨酸不仅是蛋白质合成所必需的，而且其代谢通过单碳库与中心和核苷酸代谢直接相关。此外，虽然人类细胞对高浓度的甘氨酸具有高度耐受性，但包括分枝杆菌在内的细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，我们将研究甘氨酸代谢和解毒不仅与结核分枝杆菌，而且对其他致病分枝杆菌。通过这样做，我们打算确定和阐明与不同分枝杆菌感染相关的分枝杆菌生理学的更一般方面，具体而言，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）代谢和生理学如何在细菌水平上对甘氨酸的毒性水平的挑战做出反应，以及如何与抗生素治疗协同作用，（iii）在实验感染期间削弱分枝杆菌甘氨酸代谢/解毒的影响。从长远来看，我们将阐明建立完整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.