Structure based virtual screening identifies small molecule effectors for the sialoglycan binding protein Hsa

Area of Science:

• Microbiology
• Cardiovascular Diseases
• Drug Discovery

Background:

• Infective endocarditis (IE) is a serious cardiovascular disease often caused by viridans group streptococci.
• Serine-rich repeat (SRR) proteins on bacteria like Streptococcus gordonii are crucial for attaching to human platelets, aiding disease progression.
• Current treatments lack anti-adhesive drugs targeting this bacterial attachment mechanism.

Purpose of the Study:

• To identify novel small molecules that can inhibit the Hsa adhesin protein from Streptococcus gordonii.
• To find potential anti-infective agents that block bacterial adhesion to human platelets.

Main Methods:

• Structure-based virtual screening using ensemble docking and consensus scoring was employed.
• In vitro assays were used to test the ability of identified compounds to displace the native ligand (sialyl-T antigen).
• Hierarchical clustering based on MACCS fingerprints was used to analyze the chemical diversity of the identified compounds.

Main Results:

• Nine compounds were identified that successfully displaced the native ligand and competitively bind to the Hsa adhesin.
• Eight of the identified compounds possess novel chemical scaffolds, distinct from the native ligand.
• The study demonstrates that SRR adhesins can be targeted by diverse small molecules.

Conclusions:

• Small molecules can effectively inhibit SRR adhesin proteins, preventing bacterial adhesion.
• This research opens new pathways for developing anti-infective drugs against infective endocarditis.
• Targeting bacterial adhesins offers a promising strategy for novel therapeutic interventions.