New Broad-Spectrum Antibiotics Containing a Pyrrolobenzodiazepine Ring with Activity against Multidrug-Resistant...

Area of Science:

• Medicinal Chemistry
• Microbiology
• Drug Discovery

Background:

• Urgent need for novel antibiotic classes due to dwindling pipeline.
• Rise of multidrug-resistant (MDR) Gram-negative pathogens poses a significant global health threat.
• WHO priority pathogens require immediate therapeutic interventions.

Purpose of the Study:

• To identify and characterize a new class of broad-spectrum antibacterial agents.
• To evaluate the activity of modified pyrrolobenzodiazepines against MDR Gram-negative and Gram-positive bacteria.
• To establish structure-activity relationships for improved Gram-negative activity.

Main Methods:

• Synthesis of modified pyrrolobenzodiazepines with C8-linked aliphatic heterocycles.
• Determination of minimum inhibitory concentrations (MICs) against MDR bacterial panels.
• Assessment of bactericidal kinetics and mechanism of action (DNA gyrase inhibition).

Main Results:

• Modified pyrrolobenzodiazepines demonstrated broad-spectrum activity, including against WHO priority pathogens.
• Lead compounds showed potent activity (MICs 0.125–2 mg/L) against MDR Gram-negative bacteria (excluding *P. aeruginosa*) and MDR Gram-positive species (MICs 0.03–1 mg/L).
• Rapid bactericidal effect observed for *Acinetobacter baumannii* and *Klebsiella pneumoniae*; DNA gyrase inhibition confirmed.

Conclusions:

• Modified pyrrolobenzodiazepines represent a novel chemical scaffold for developing new antibiotics.
• The third ring modification is crucial for enhanced Gram-negative activity.
• This class of compounds holds potential to replenish the antibiotic pipeline against MDR pathogens.