Targeting the allosteric control of alarmone synthetases to tackle bacteria persistence

The current crisis of antibiotic resistance has prompted the need to devise strategies to tackle the problem, with a strong focus on developing novel antibiotics. However, one major obstacle that is much overlooked is that persister bacterial cells are refractory to antibiotic treatment. A family of intracellular chemicals called alarmones are the master regulators for such persistence. Alarmones possess phosphate groups and enable pathogens to survive after prolonged exposure to antibiotics. Despite this key role, little is known about the enzymes which catalysethe manufacture of alarmones. There is a specific and significant need to study how these enzymes work and this information would help in the design of new antibiotics targeting the alarmone pathway.

We will apply combined techniques including F NMR spectroscopy and X-ray protein crystallography to reveal atom-level information about how phosphoryl groups are transferred and how alarmones are made. This work will advance knowledge of enzymes from the RelA/SpoT homologue (RSH) superfamily involved in alarmone regulation.

This data will form a sound basis for future drug design to combat antibiotic resistence.