Dynamics of the adhesion complex of the human pathogens Mycoplasma pneumoniae and Mycoplasma genitalium.

Summary

Cryo-EM mapping identified a closed-state–specific epitope on the P1 adhesin whose antibody binding halts gliding and induces detachment of Mycoplasma cells. Polyclonal antibodies to other domains were ineffective, and conserved transmembrane mutations altered adhesion, revealing conformational cycling as an actionable target.

Key Findings

• Cryo-EM structure of P1 adhesin bound to P1/MCA4 Fab reveals an epitope confined to the C-domain accessible only in closed conformation.
• Anti–C-domain antibodies disrupt conformational transitions required for adhesion/gliding, stopping motility and inducing detachment.
• Polyclonal antibodies to P1 N-domain or P40/P90 ectodomain show little effect; conserved Engelman motif mutations in P110 alter adhesion/motility.

Clinical Implications

Antibodies or molecules stabilizing non-adhesive conformations of the adhesin complex could impede colonization and disease; epitope-focused vaccine or therapeutic antibody development is rational.

Limitations

• Lacks in vivo infection models to confirm protection or therapeutic efficacy
• Translational development of conformationally selective antibodies or small molecules remains to be demonstrated

Future Directions

Develop conformation-specific antibodies/small molecules that lock the adhesion complex in a non-functional state; evaluate protection in animal models of atypical pneumonia.