A global stress alarmone couples nutrient limitation to suppression of social signaling in bacteria

Bacterial quorum sensing (QS) governs metabolically costly cooperative behaviors such as biofilm formation and virulence. How bacteria prevent unwanted QS under nutrient limitation is unknown. Using Xanthomonas oryzae pv. oryzae , a pathogen of rice, as a model, we identify the stringent response alarmone ppGpp as a metabolic checkpoint that directly inhibits diffusible signal factor (DSF)-mediated QS. The loss of the alarmone synthetase RelA increased DSF production, unwound QS-responsive genes, and enhanced social behaviors at stationary phase. Structural, biochemical, and genetic studies showed that ppGpp directly inhibits phosphodiesterase activity of the QS response regulator RpfG, elevating the cyclic di-GMP levels. Increase in cyclic di-GMP reduces the DNA binding by the QS transcriptional regulator Clp, disrupting a positive auto-regulatory loop required for DSF synthesis and social behavior. This may be a conserved mechanism used by bacteria to limit social behaviors with saving of energy when resources are low or under stringent condition.