Riboswitch-controlled glycine metabolism in pathogenic mycobacteria.

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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.