C8-Linked Pyrrolobenzodiazepine Monomers with Inverted Building Blocks Show Selective Activity against Multidrug...

Area of Science:

• Medicinal Chemistry
• Antimicrobial Drug Discovery
• Molecular Biology

Background:

• Antimicrobial resistance (AMR) is a critical global health threat, necessitating the development of new treatments for multidrug-resistant (MDR) pathogens.
• Pyrrolobenzodiazepines (PBDs) are a class of natural products with emerging antibacterial properties, particularly against Gram-positive strains.

Purpose of the Study:

• To synthesize and evaluate novel C8-linked PBD biaryl conjugates with inverted building block orientations.
• To establish structure-activity relationships (SAR) for PBDs against MDR Gram-positive bacteria.
• To investigate the mechanism of action and potential toxicity of these PBD derivatives.

Main Methods:

• Synthesis of four novel PBD structures with inverted amide bonds.
• Determination of minimum inhibitory concentrations (MICs) against MDR Gram-positive strains.
• In vitro DNA gyrase inhibition assays and molecular modeling studies.
• Assessment of eukaryotic toxicity and DNA stabilization potential.

Main Results:

• Synthesized PBDs exhibited MICs ranging from 0.125 to 32 μg/mL against MDR Gram-positive pathogens.
• Single amide bond inversion decreased activity, while double inversion restored potent antibacterial effects.
• Compounds demonstrated a bactericidal mode of action, inhibited DNA gyrase in vitro, and showed no eukaryotic toxicity.
• Molecular modeling supported the interaction of PBDs with both wild-type and mutant DNA gyrases.

Conclusions:

• The orientation of building blocks in PBDs significantly impacts antibacterial activity, with double inversions being beneficial for MDR pathogens.
• DNA gyrase inhibition is a likely mechanism of action for these novel PBDs, offering a promising avenue for combating resistant infections.
• These findings provide crucial SAR insights for the future design of PBD-based antibacterial agents.