Phosphorylation Mechanisms in Bacterial Pathogenicity

Bacterial pathogens employ reversible phosphorylation on serine, threonine and tyrosine residues to control virtually every aspect of virulence, from cell‐surface architecture to stress adaptation. Eukaryote‐like serine/threonine kinases (STKs) and tyrosine kinases work in concert with cognate phosphatases to form intricate signalling circuits that sense environmental cues, govern the synthesis of capsules, biofilms and toxins, and direct the assembly of division and secretion machineries. Phosphorylation of regulatory proteins can alter DNA binding, enzyme activity or protein–protein interactions, thereby reprogramming gene expression programmes and metabolic fluxes to promote survival within hostile host niches. Cross‐talk between different kinase families and two‐component systems amplifies and integrates signals, while autophosphorylation events ensure rapid feedback control. These mechanisms underpin antibiotic resistance, modulation of innate‐immune evasion and dissemination strategies. Understanding bacterial phosphorylation networks thus holds global significance, offering routes to novel antimicrobials, antibiotic‐resistance breakers and vaccine adjuvants by targeting kinases, phosphatases or their key substrates.

Research from Nature Portfolio

Recent studies have elucidated how serine/threonine kinase activity shapes polysaccharide‐based virulence. In Streptococcus suis, the STK‐phosphorylated protein CcpS was shown to bind and inhibit its cognate phosphatase CpsB when unmodified, thereby maintaining CpsD in a phosphorylated state that upholds capsule biosynthesis. Structural analysis revealed an intrinsically disordered N‐terminal region harbouring two threonine sites whose phosphorylation status dictates CcpS–CpsB interplay and controls the Wzx–Wzy export pathway. This work links STK1 signalling directly to capsule production and illuminates a modular mechanism by which bacteria can tune surface‐exposed virulence factors.

Another investigation explored small‐molecule inhibition of STK1 in methicillin‐resistant Staphylococcus aureus. A quinazoline derivative, Inh2-B1, was found to bind the ATP‐binding cleft of STK1, effectively abolishing its kinase activity. Although neither inhibitor nor cephalosporin alone protected against lethal infection in animal models, combined treatment restored β-lactam susceptibility and conferred significant in vivo protection. This approach exemplifies the therapeutic promise of kinase inhibitors as antibiotic‐resistance breakers.

Phosphorylation Mechanisms in Bacterial Pathogenicity publication trend

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

Technical terms

Serine/threonine kinase (STK): An enzyme that transfers phosphate groups to serine or threonine residues on target proteins, regulating diverse cellular processes.

BY‐kinase: A bacterial tyrosine kinase that autophosphorylates and phosphorylates substrates on tyrosine residues, often controlling cell‐surface assembly or stress responses.

Autophosphorylation: A self‐modification process in which a kinase phosphorylates one of its own amino acid residues to regulate its activity or interactions.

Capsular polysaccharide (CPS): A carbohydrate layer surrounding some bacteria that shields against host immunity and promotes virulence; its synthesis is often controlled by phosphorylation networks.

Phosphatase: An enzyme that removes phosphate groups from proteins, counterbalancing kinase activity and enabling dynamic control of signalling pathways.

References

1. Mechanisms of Virulence Reprogramming in Bacterial Pathogens. Annual Review of Microbiology (2023).
2. A link between STK signalling and capsular polysaccharide synthesis in Streptococcus suis. Nature Communications (2023).
3. A novel STK1-targeted small-molecule as an “antibiotic resistance breaker” against multidrug-resistant Staphylococcus aureus. Scientific Reports (2017).
4. Connection between protein-tyrosine kinase inhibition and coping with oxidative stress in Bacillus subtilis. Proceedings of the National Academy of Sciences of the United States of America (2024).
5. Cross-phosphorylation of bacterial serine/threonine and tyrosine protein kinases on key regulatory residues. Frontiers in Microbiology (2014).