Repurposing bleomycin against Acinetobacter baumannii HisG: computational, biophysical, and antibacterial evidence

Area of Science:

• Microbiology
• Biochemistry
• Drug Discovery

Background:

• Acinetobacter baumannii poses a significant clinical threat due to rising antibiotic resistance.
• Conventional treatments are becoming less effective, necessitating novel therapeutic strategies.
• The histidine biosynthesis pathway is a viable target as it's essential for bacteria but absent in humans.

Purpose of the Study:

• To investigate the potential of Bleomycin, an anticancer drug, to inhibit ATP phosphoribosyltransferase (HisG) in A. baumannii.
• To explore Bleomycin as a novel antibacterial agent targeting the histidine biosynthesis pathway.

Main Methods:

• Virtual screening and molecular interaction analysis to predict Bleomycin-HisG interaction.
• Surface Plasmon Resonance (SPR) to determine binding kinetics (KD).
• In vitro antibacterial assays to evaluate growth inhibition (MIC) and bacteriostatic activity.

Main Results:

• Bleomycin exhibited strong binding to the HisG active site, confirmed by molecular docking and SPR (KD = 270 nM).
• Bleomycin significantly inhibited A. baumannii growth in vitro, with a Minimum Inhibitory Concentration (MIC) of 7.8125 µg/mL.
• Time-dependent assays showed strong bacteriostatic activity at and above MIC concentrations.

Conclusions:

• Bleomycin effectively interacts with the HisG active site and suppresses A. baumannii growth.
• Bleomycin demonstrates potential as a HisG-associated antibacterial agent for multidrug-resistant pathogens.
• This study supports the repurposing of existing drugs for novel antibacterial therapies.