What Is an Alarmone and What Does It Do?

Alarmones are intracellular signaling molecules that function as internal alert systems, primarily in bacteria but also in plant chloroplasts and some archaea. They are produced when an organism encounters stressful conditions, such as nutrient scarcity. The production of alarmones initiates a broad reprogramming of cellular activities, shifting priorities from growth and division to conservation and survival.

Understanding the Stringent Response

When a microorganism faces a threat like starvation, it triggers a defense program known as the stringent response. This process shifts the cell from active growth to a state of maintenance and survival. The triggers include nutritional stresses, such as a lack of amino acids, fatty acids, or iron, as well as environmental factors like heat shock or sudden pH changes.

The stringent response is characterized by a halt in cell growth and a reprogramming of gene expression. The cell reduces the production of molecules associated with proliferation, like ribosome components and DNA building blocks. Cellular resources are instead redirected toward synthesizing molecules needed for stress tolerance, such as amino acids that are in short supply, allowing the organism to conserve energy.

Primary Alarmones and Their Production

The molecules that drive the stringent response are guanosine tetraphosphate (ppGpp) and guanosine pentaphosphate (pppGpp), collectively referred to as (p)ppGpp. These alarmones are created from guanosine triphosphate (GTP) and guanosine diphosphate (GDP), which are central to RNA synthesis and cellular energy transfer. Their production signals that a stressful condition has been detected.

The synthesis and degradation of these alarmones are managed by RelA/SpoT Homology (RSH) proteins. In many bacteria, two enzymes, RelA and SpoT, control (p)ppGpp levels. RelA is activated by amino acid starvation when a ribosome stalls during protein synthesis. SpoT is bifunctional, meaning it can both create and degrade (p)ppGpp, and it responds to a wider array of stresses like carbon or phosphate shortages. This allows SpoT to fine-tune alarmone concentrations, while in some bacteria, a single RSH enzyme performs both functions.

How Alarmones Regulate Cellular Processes

Once produced, (p)ppGpp alarmones exert control by directly interacting with and modifying cellular machinery to halt growth. A main target is RNA polymerase (RNAP), the enzyme that transcribes DNA into RNA. Alarmones alter RNAP’s function and influence other core processes in several ways:

• They reduce the transcription of genes needed for rapid growth, such as those for ribosomal RNA (rRNA) and transfer RNA (tRNA).
• They increase the transcription of genes involved in stress mitigation, such as those that synthesize scarce amino acids.
• They can inhibit enzymes in the GTP synthesis pathway, causing a drop in cellular GTP levels that shuts down ribosome production.
• They directly inhibit enzymes involved in DNA replication, such as DNA primase, which slows or halts the cell cycle.
• They bind to translation-related factors to modulate the efficiency of protein synthesis at the ribosome.

The Wider Impact of Alarmone Signaling

The stringent response has implications for how bacteria interact with their environment and hosts, including bacterial virulence, biofilm formation, and antibiotic tolerance. Biofilms are protective communities that shield bacteria from immune cells and antibiotics. The production of (p)ppGpp often signals bacteria to switch from a free-living state to forming these resilient communities.

This system contributes to bacterial persistence, where a subpopulation of bacteria becomes dormant and tolerant to antibiotics. These “persister” cells are not genetically resistant but can survive treatment and repopulate an infection, leading to chronic issues. Because the stringent response is central to these survival strategies, the enzymes that produce alarmones are promising targets for new antimicrobial therapies.

Alarmone signaling is not exclusive to bacteria, as a similar system exists in plant chloroplasts, which descended from ancient bacteria. In plants, alarmones accumulate in response to stresses like high salinity, drought, and UV radiation. This system helps plants adapt by regulating gene expression and photosynthetic activity within the chloroplast.