Two-Component Regulatory Systems in Antimicrobial Resistance

Two-component regulatory systems constitute a widespread mechanism by which bacteria detect and adapt to antimicrobial threats. Each system comprises a membrane-associated sensor histidine kinase that perceives external stimuli and a cognate response regulator that orchestrates transcriptional responses. Upon signal recognition, the kinase autophosphorylates and transfers the phosphoryl group to the regulator, triggering changes in gene expression. These programmes often control cell-envelope modifications, efflux pump production, biofilm formation and virulence factor synthesis, thereby contributing to intrinsic and acquired resistance. By fine-tuning the bacterial response to antibiotics and host-derived peptides, two-component systems represent both a key axis of microbial survival and an attractive target for novel antimicrobial strategies.

Research from Nature Portfolio

Structural and functional dissection of a Bce-type antimicrobial peptide resistance module has revealed the first cryo-EM structure of a complete complex formed by an ABC transporter and its partner histidine kinase. This work demonstrated how nucleotide binding primes the complex for activation and uncovered extensive conformational flexibility within the sensor kinase. Biochemical assays further showed that each membrane component exerts reciprocal control, yielding a tightly regulated resistance apparatus. In a separate study of Lacticaseibacillus paracasei, two paralogous modules governing response to lantibiotics—PsdRSAB and ApsRSAB—were shown to cross-regulate promoters of key detoxification and cell-membrane maintenance genes. Promoter-binding assays confirmed that each response regulator recognises overlapping DNA motifs, providing a mechanistic basis for regulatory overlap between related systems.

Two-Component Regulatory Systems in Antimicrobial Resistance publication trend

The graph below shows the total number of articles in two-component regulatory systems in antimicrobial resistance across all publications each year (not limited to Nature Index journals).

Technical terms

Two-component system (TCS): A signalling module comprising a sensor histidine kinase and a response regulator that controls gene expression in response to environmental cues.

Histidine kinase (HK): A membrane-associated sensor protein that autophosphorylates on a conserved histidine residue upon detecting a stimulus.

Response regulator (RR): A cytosolic transcription factor that receives a phosphoryl group from its cognate kinase to modulate target gene transcription.

ABC transporter: An ATP-binding cassette transporter that can function in antimicrobial peptide efflux and signal transduction in conjunction with TCSs.

Peptidoglycan: A mesh-like polymer forming the bacterial cell wall, often remodelled under TCS control to alter permeability and antibiotic susceptibility.

References

1. Architecture of a complete Bce-type antimicrobial peptide resistance module. Nature Communications (2023).
2. Cross-regulation of Aps-promoters in Lacticaseibacillus paracasei by the PsdR response regulator in response to lantibiotics. Scientific Reports (2024).
3. Selective Bacteriocins: A Promising Treatment for Staphylococcus aureus Skin Infections Reveals Insights into Resistant Mutants, Vancomycin Resistance, and Cell Wall Alterations. Antibiotics (2023).
4. Staphylococcus aureus susceptibility to complestatin and corbomycin depends on the VraSR two-component system. Microbiology Spectrum (2023).