Targeting bacterial stress responses to reduce virulence

To cope with stress, bacteria activate a molecular alarm system controlled by the enzymes Rel and RelA. These enzymes alternate between active and inactive conformations to regulate the production of (p)ppGpp, a small molecule that plays a central role in bacterial adaptation and virulence.

The team led by Abel Garcia-Pino (WEL Research Institute – ULB) demonstrated that this alarm signal can be directly modulated by controlling the balance between the active and inactive states of Rel and RelA. Maintaining RelA in an inactive conformation prevented the synthesis of (p)ppGpp and significantly reduced the virulence of E. coli in an animal model. Conversely, stabilizing a Rel conformation that promoted the production of this signal increased bacterial virulence.

These findings open a new route to combat bacterial infections by targeting the stress response itself rather than bacterial survival directly.

Reference: Van Nerom et al, Nanobody-mediated control of long RSH Rel and RelA catalysis by restriction of their conformational landscape, Nat Commun (2026), online ahead of print