Hit optimization by dynamic combinatorial chemistry on Streptococcus pneumoniae energy-coupling factor transporter...

Area of Science:

• Biochemistry and structural biology
• Microbiology
• Medicinal chemistry

Background:

• The energy-coupling factor (ECF) transporter ECF-PanT in Streptococcus pneumoniae is a highly dynamic transmembrane complex.
• Targeted drug discovery is crucial for developing new antimicrobial agents.

Purpose of the Study:

• To apply target-directed dynamic combinatorial chemistry (tdDCC) for the first time to the ECF-PanT transporter.
• To identify and optimize inhibitors of ECF-PanT using tdDCC.
• To characterize the identified inhibitors and elucidate their binding mode.

Main Methods:

• Application of target-directed dynamic combinatorial chemistry (tdDCC).
• Hit identification and optimization strategy.
• Cytotoxicity characterization of lead compounds.
• Computational modeling and docking studies on the ECF-PanT crystal structure.

Main Results:

• Successful application of tdDCC to the ECF-PanT complex.
• Identification of optimized ECF inhibitors with enhanced activity.
• Characterization of compound cytotoxicity.
• Computational analysis rationalizing inhibitor binding modes, highlighting the role of the acylhydrazone linker.

Conclusions:

• tdDCC is an effective strategy for discovering and optimizing inhibitors of dynamic protein complexes like ECF-PanT.
• The identified inhibitors show promising activity and favorable binding interactions.
• Further development of these inhibitors could lead to novel therapeutic agents against Streptococcus pneumoniae infections.