Exploring Alternative Pathways to Target Bacterial Type II Topoisomerases Using NBTI Antibacterials: Beyond...

Area of Science:

• Medicinal Chemistry
• Molecular Biology
• Structural Biology

Background:

• Novel bacterial topoisomerase inhibitors (NBTIs) represent a promising new class of antibacterial agents.
• NBTIs target essential bacterial type II topoisomerases, including DNA gyrase and topoisomerase IV.
• Previous studies revealed halogen atoms in NBTIs form strong halogen bonds with DNA gyrase.

Purpose of the Study:

• To investigate the role of interactions beyond halogen bonding in NBTI activity.
• To explore alternative interactions, such as hydrogen-bonding and hydrophobic interactions.
• To understand the structure-activity relationship of NBTIs by modifying the phenyl RHS moiety.

Main Methods:

• Crystallography was used to analyze the complex of an NBTI ligand with DNA gyrase and DNA.
• Various non-halogen groups were introduced at the para-position of the phenyl RHS moiety.
• Computational analysis was performed to assess potential binding interactions.

Main Results:

• The para-position halogen atom of the phenyl RHS moiety forms strong, symmetrical bifurcated halogen bonds with the enzyme.
• These halogen bonds are critical for the high enzyme inhibitory potency and antibacterial activity of NBTIs.
• Designed NBTIs with non-halogen groups could not form hydrogen bonds but could form hydrophobic interactions.
• Halogen-bonding interactions were identified as the most preferred mode of binding.

Conclusions:

• Halogen bonds are the primary drivers of NBTI potency and antibacterial activity.
• The binding pocket of bacterial topoisomerases favors halogen bonding over hydrogen bonding for NBTIs.
• Further NBTI development should focus on optimizing halogen-bonding interactions for enhanced efficacy.