Stress-Induced Iron-Sulfur Cluster Damage as a Conserved Trigger of the Stringent Response

Pathogenic bacteria rely on the stringent response to adapt to the complex and fluctuating conditions encountered within the host. However, the mechanisms by which the stringent response senses host-induced stress remain poorly understood. Here, we identify iron-sulfur (Fe-S) cluster damage as a conserved trigger of the stringent response in major Gram-negative pathogens, including Salmonella enterica, Enterobacter cloacae, and Klebsiella pneumoniae. We demonstrate that Fe-S cluster disruption--caused by oxidative stress or metal imbalance--restricts the intracellular pools of sulfur-containing and branched-chain amino acids, thereby activating the ribosome-associated (p)ppGpp synthetase RelA. Furthermore, we show that iron availability governs recovery from Fe-S cluster damage, modulating the dynamics of the stringent response. Finally, we emphasize the dual role of (p)ppGpp in transcriptional regulation, enhancing bacterial fitness during Fe-S cluster stress while simultaneously promoting virulence by upregulating the SPI-2 type III secretion system. Together, these findings uncover a conserved mechanism by which pathogenic bacteria integrate metabolic stress into adaptive gene regulation and virulence, positioning Fe-S cluster integrity as a pivotal node linking environmental sensing to transcriptional control during infection.