UKRI FLF renewal: Energy Metabolism and Antibiotic Action in the Tuberculosis Pathogen

Scientific background
Bioenergetic systems give living organisms the energy they need to live and grow. For organisms that grow with air, bioenergetic systems are composed of electron transport chains that take electrons from food molecules and pass them to oxygen, using the released energy to pump protons across a membrane. A different system, ATP synthase, uses these protons to power the addition of phosphate to ADP to make ATP. ATP then powers the cell. Humans have these systems, but so do bacterial pathogens such as tuberculosis. A number of new drugs against tuberculosis have been recently released that target bioenergetics. A notable example is bedaquiline that inhibits ATP synthase.
A major achievement in the first phase of this fellowship, which is still active, was to set up biophysical methods to measure bioenergetics in living tuberculosis cells and use these methods to understand the mechanism of bedaquiline. In this extension, we will be building on these foundations to make further fundamental discoveries in how tuberculosis energises itself, use these discoveries to understand combinations of antibiotics that target bioenergetics, and just as importantly for this scheme, use the time and space provided by the FLF to keep developing the team members.

Overarching UKRI FLF Renewal aim:
To use our biophysical methods established in the first phase of the FLF project to understand fundamental principles underlying mycobacterial bioenergetics and how those principles apply to bioenergetic-targeting antibiotics used alone and in combination.

Theme 1: Using the biophysical tools developed in the first phase of the FLF to understand more about the fundamental biology of mycobacteria
We have teamed up with Dr Roger Springett to develop and apply methods to measure the state of the mycobacterial electron transport chain in vivo. With this system we discovered that mycobacteria possess an ability to rapidly reroute electrons through their electron transport...