Targeting the BspC-vimentin interaction to develop anti-virulence therapies during Group B streptococcal meningitis

Area of Science:

• Microbiology and Infectious Diseases
• Drug Discovery and Development
• Molecular Biology

Background:

• Bacterial infections and rising antibiotic resistance pose significant global health threats.
• Pathogen adhesins are crucial for host cell attachment and disease initiation, representing viable therapeutic targets.
• Group B Streptococcus (GBS) is a leading cause of bacterial neonatal meningitis, with its BspC adhesin mediating interaction with host vimentin.

Purpose of the Study:

• To identify the specific domain and binding site of the BspC adhesin responsible for GBS interaction with host cells.
• To develop novel therapeutic strategies targeting the pathogen-host interface to combat GBS meningitis.

Main Methods:

• Site-directed mutagenesis to pinpoint the vimentin binding pocket within the BspC variable (V-) domain.
• Virtual structure-based drug screening to identify compounds targeting the identified binding pocket.
• In vivo models to assess the efficacy of identified compounds in blocking GBS adherence and brain entry.

Main Results:

• The BspC V-domain was confirmed to contain the vimentin binding site essential for GBS adherence to brain endothelium.
• A specific binding pocket within the V-domain was identified as critical for GBS host cell interaction and meningitis development.
• Virtual screening successfully identified compounds that effectively blocked GBS adherence and brain invasion in vivo.

Conclusions:

• Targeting the BspC adhesin-vimentin interaction site presents a promising anti-virulence therapeutic strategy against GBS neonatal meningitis.
• The identified compounds demonstrate potential for developing novel treatments that inhibit bacterial pathogenesis at the pathogen-host interface.