Metabolic Warfare: Outmanoeuvring M. tuberculosis in the Fight Against Antibiotic Resistance
Posted on March 24, 2025 by Jordan Pascoe
To mark World TB Day the Society asked Jordan Pascoe, whose research, 'Metabolism triggers phenotypic resistance in Mycobacterium tuberculosis', will be presented at the Microbiology Society's Annual conference, to provide insight into their research and the importance of understanding antibiotic resistance in TB.
My name is Jordan Pascoe, I’m a PhD student in Dr Dany Beste's team at the University of Surrey, UK. As self-described "bacterial dieticians," our goal is to define the nutritional requirements and metabolic pathways that are essential to pathogenic mycobacteria in their hosts, with the overall goal of translating this fundamental science into effective treatment approaches.
Each year we commemorate World TB Day on 24 March, as this marks the day in 1882 when Dr Robert Koch first announced that he had discovered Mycobacterium tuberculosis, the bacterium, that causes Tuberculosis — the likely number one cause of death by infectious disease in 2025. Tuberculosis disproportionately impacts society's most marginalised populations but sadly only receives a fraction of the funding and resources allocated to other diseases that affect individuals across all socioeconomic levels. In 2024, the UK saw an 11% increase in the number of Tuberculosis cases. Globally, Tuberculosis cases increased to their highest recorded levels. Years of under-funding has meant that there are limited options for the prevention and treatment of Tuberculosis, and we still lack fundamental information about this pathogen’s basic microbiology.
M. tuberculosis is an unusual bacterial pathogen which has the remarkable ability to cause both acute life-threatening disease and symptomless infections that can persist for the lifetime of the human host. To do this, M. tuberculosis exhibits extraordinary metabolic flexibility to survive the onslaught of host environmental stresses and antibiotics, — this is why prolonged multi-drug therapy for a minimum of 6-months is required to cure tuberculosis. A significant impediment to the development of shorter, more effective tuberculosis therapies, is that we lack a complete understanding as to what M. tuberculosis is utilising in the host, and how its metabolism adapts in response to a changing host environment to sustain itself during these different stages of infection.
To define the metabolic capabilities of mycobacteria, our research group has developed an experimental platform using a bioreactor for systems biology studies of M. tuberculosis in different environmental conditions. Our continuous culture chemostat model maintains M. tuberculosis in a perpetual state of replication and therefore very amenable to systems level studies, such as multi-omics studies and 13C-Metabolic Flux Analysis. For 13C-Metabolic Flux Analysis M. tuberculosis is fed non-radioactive isotopic labelled (e.g. 13C) nutrient sources to track these nutrients through metabolic pathways, through to energy and biomass formation, that can be measured using mass spectrometry. This generates a metabolic fingerprint—which we input into a computational model of M. tuberculosis metabolism to allow us to define the metabolic state of the bacteria in different conditions. We have also developed this method for use when M. tuberculosis is growing within its human host cell, gaining insight into the novel mechanisms this pathogen possesses to maintain infection. More recently, our research group has joined forces with Analytical Chemists, and together we are developing state-of-the-art mass spectrometry methods to measure metabolism at a single cell level to explore metabolic heterogeneity during host infection.
The BCG vaccine is the only available vaccine for tuberculosis and has variable efficacy depending on your geographical location. It unfortunately performs worse in areas of the world with high cases numbers. Without an effective vaccine we are reliant on antibiotic treatment to control tuberculosis and antibiotic resistance is a major impediment. We now have incurable 'extremely drug-resistant' strains circulating in many countries, including the UK. We therefore urgently need shortened, less toxic tuberculosis treatments. The principal reason why treatment needs to be so lengthy is that M. tuberculosis has a remarkable ability to effectively tolerate and survive in the presence of antibiotics. The hypothesis of my PhD research project is that this antibiotic survival is due to the metabolic adaptive response of M. tuberculosis.
I have shown that different carbon sources impact on the antibiotic killing of M. tuberculosis. Surprisingly, addition of gluconeogenic substrates resulted in treatment failure, and the emergence antibiotic resistance after only 11 days treatment. Applying 13C-Metabolic Flux Analysis, I have demonstrated that metabolic remodelling is driving this phenotype and have identified a specific metabolic pathway underpinning this emergence of resistance. In collaboration with Professor Miraz’s Team at King’s College London, UK, we've utilised this knowledge to engineer a series of compounds that are potent antibiotic adjuvants which enhance the antibiotic killing of TB and act as antibiotic resistance breakers.
Overall, my research provides a new understanding of the mechanistic basis of the interaction between antibiotics and bacterial metabolism. It can be translated into impact through the identification of new therapeutic targets and co-treatments which enhance antibiotic killing and interfere with antibiotic resistance. Thereby improving treatment so urgently needed if we are to have any chance of meeting the WHO End-TB targets.
Jordan will be presenting their research, 'Metabolism triggers phenotypic resistance in Mycobacterium tuberculosis', at 10:45 on Tuesday 01 April at the Microbiology Society Annual Conference in Liverpool.