Covalent Proteomimetic Inhibitor of the Bacterial FtsQB Divisome Complex

Area of Science:

• Microbiology and Molecular Biology
• Drug Discovery and Development

Background:

• The rise of multidrug-resistant bacteria necessitates novel antibiotic targets.
• The bacterial divisome, crucial for cell division, presents a promising target.
• The FtsQB subcomplex is vital for divisome assembly and peptidoglycan synthesis in *E. coli*.

Purpose of the Study:

• To design and synthesize a novel inhibitor targeting the FtsQB subcomplex.
• To validate the inhibitor's efficacy against *E. coli* and its virulence.

Main Methods:

• Structure-based design of a macrocyclic covalent inhibitor.
• Stabilization of the inhibitor's bioactive conformation via cross-linking.
• Assessment of inhibitor's effect on bacterial growth, FtsB localization, and *E. coli* infection in zebrafish.

Main Results:

• A novel covalent inhibitor irreversibly blocks the FtsQ-FtsB interaction.
• The inhibitor reduces growth of an outer membrane-permeable *E. coli* strain and disrupts FtsB localization.
• The inhibitor demonstrates efficacy in reducing *E. coli* infection in a zebrafish model.

Conclusions:

• This study presents the first-in-class inhibitor of a bacterial divisome protein-protein interaction.
• Proteomimetic molecules, particularly covalent inhibitors, show potential for targeting challenging bacterial proteins.
• The developed covalent inhibitor strategy offers a promising avenue for future antibiotic development against protein-protein interactions.