Riboswitch-controlled glycine metabolism in pathogenic mycobacteria.
Lead Research Organisation:
University College London
Department Name: Structural Molecular Biology
Abstract
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.
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.
Technical Summary
Identifying and characterising novel high-value targets for antibiotic discovery is a strategic priority to combat mycobacterial diseases such as tuberculosis, leprosy, Buruli ulcer, and soft tissue and lung infections caused by Mycobacterium abscessus. Together these diseases affect millions of people every year, globally. Antibiotic resistance and intrinsic antibiotic resistance represent major problems for the management of various mycobacterial diseases.
Mycobacterial metabolism constitutes an important and validated area for the development of novel drugs. The goal of this proposal is to understand how glycine metabolism and detoxification promotes mycobacterial growth and virulence. Glycine occupies a key position in metabolism, as it is not only essential for protein synthesis, but its metabolism is directly linked to central and nucleotide metabolism, via the one-carbon pool and folates. This proposal focusses on four distinct pathogenic mycobacteria (Mycobacterium tuberculosis, M. ulcerans, M. mageritense and M. houstonense), instead of a single species. While M. tuberculosis and M. ulcerans are slow growing species, M. mageritense and M. houstonense are fast growers and intrinsically multi-drug resistant. These species were chosen as they seem to have two copies of the enzyme interconverts glycine into serine, serine hydroxymethyltransferase. Importantly, two copies of this enzyme are only found in pathogenic but not environmental mycobacteria, hinting at an important role during infection. By employing multiple distinct yet related pathogenic species, we intend to identify and characterise more general aspects of mycobacterial physiology relevant to infection, but dispensable in soil-dwelling and waterborne environmental species.
Our results might serve as starting point for the discovery of novel and improved antibiotics that work by blocking glycine metabolism, which could synergise with host-imposed glycine toxicity and existing antibiotics.
Mycobacterial metabolism constitutes an important and validated area for the development of novel drugs. The goal of this proposal is to understand how glycine metabolism and detoxification promotes mycobacterial growth and virulence. Glycine occupies a key position in metabolism, as it is not only essential for protein synthesis, but its metabolism is directly linked to central and nucleotide metabolism, via the one-carbon pool and folates. This proposal focusses on four distinct pathogenic mycobacteria (Mycobacterium tuberculosis, M. ulcerans, M. mageritense and M. houstonense), instead of a single species. While M. tuberculosis and M. ulcerans are slow growing species, M. mageritense and M. houstonense are fast growers and intrinsically multi-drug resistant. These species were chosen as they seem to have two copies of the enzyme interconverts glycine into serine, serine hydroxymethyltransferase. Importantly, two copies of this enzyme are only found in pathogenic but not environmental mycobacteria, hinting at an important role during infection. By employing multiple distinct yet related pathogenic species, we intend to identify and characterise more general aspects of mycobacterial physiology relevant to infection, but dispensable in soil-dwelling and waterborne environmental species.
Our results might serve as starting point for the discovery of novel and improved antibiotics that work by blocking glycine metabolism, which could synergise with host-imposed glycine toxicity and existing antibiotics.
