Stringent Response Mechanisms in Bacterial Systems

The stringent response is a universal bacterial stress adaptation programme triggered by nutritional deprivation, environmental insult or host‐induced stress. Central to this response is the rapid accumulation of the guanosine tetraphosphate and pentaphosphate alarmones, collectively referred to as (p)ppGpp. These small molecules are synthesised and hydrolysed by members of the RelA/SpoT homolog (RSH) superfamily, which sense ribosomal cues and metabolic signals. Elevated (p)ppGpp levels reprogramme transcription by binding to RNA polymerase and modulating promoter specificity, downregulating ribosomal RNA and protein synthesis while upregulating factors for amino acid biosynthesis, stress tolerance and persistence. Beyond transcriptional control, (p)ppGpp influences ribosome assembly, translation fidelity, DNA repair pathways and toxin–antitoxin systems, thereby coordinating global physiology under stress. This multilayered regulation underpins bacterial survival in diverse niches, contributes to pathogenicity and underlies the phenotypic tolerance to antibiotics that characterises chronic and recurrent infections.

Research from Nature Portfolio

Recent studies have elucidated how structured antitoxin domains neutralise toxic small alarmone synthetases (toxSAS) by occluding substrate‐binding sites in a manner that is tightly coupled to the chemical nature of the alarmone substrate, revealing general principles for the inhibition of this emerging class of bacterial effectors. Concurrently, structural, genetic and biochemical investigations into RNA polymerase have uncovered a previously unrecognised binding site for ppGpp that is distinct from its initiation‐phase regulatory site. Binding at this elongation‐specific pocket ensures efficient coupling between transcriptional pausing and DNA repair, thereby preserving genome integrity under genotoxic stress and expanding the functional repertoire of the stringent response beyond transcription initiation.

Stringent Response Mechanisms in Bacterial Systems publication trend

The graph below shows the total number of articles in stringent response mechanisms in bacterial systems across all publications each year (not limited to Nature Index journals).

Technical terms

(p)ppGpp: Guanosine tetraphosphate and pentaphosphate alarmones that act as second messengers to reprogramme bacterial transcription, translation and metabolism under stress.

RelA/SpoT Homologs (RSH): A superfamily of bifunctional enzymes that synthesise and hydrolyse (p)ppGpp, sensing ribosomal and metabolic signals to regulate alarmone levels.

Alarmone: A signalling nucleotide, exemplified by (p)ppGpp, that orchestrates global bacterial responses to nutrient and environmental stress.

toxSAS: Toxic small alarmone synthetases found in toxin–antitoxin modules that generate lethal levels of alarmone or ppApp unless neutralised by cognate antitoxins.

Antitoxin domain: A structured protein region that binds and inhibits a toxin, often by occluding its substrate‐binding site in toxin–antitoxin systems.

Ribosomal A-site tRNA: The acceptor site on the small ribosomal subunit where deacylated transfer RNA binds, serving as the trigger for RelA activation during amino-acid starvation.

References

1. YbiB: a novel interactor of the GTPase ObgE. Nucleic Acids Research (2023).
2. The structure of DarB in complex with RelNTD reveals nonribosomal activation of Rel stringent factors. Science Advances (2023).
3. Mechanisms of neutralization of toxSAS from toxin–antitoxin modules. Nature Chemical Biology (2024).
4. Control of transcription elongation and DNA repair by alarmone ppGpp. Nature Structural & Molecular Biology (2023).
5. Ribosome•RelA structures reveal the mechanism of stringent response activation. eLife (2016).