A computer-aided drug repurposing: the antibacterial agents targeting GroEL.

Area of Science:

• Computational biology
• Drug discovery
• Antimicrobial research

Background:

• Drug repurposing (DR) provides a lower-risk, cost-effective alternative to traditional drug discovery by applying approved drugs to new indications.
• Robust computational workflows are crucial for accelerating early-stage drug repurposing and antibiotic discovery.

Purpose of the Study:

• To establish and validate a novel computational workflow for identifying non-antibacterial drugs with potential antibacterial properties.
• To explore the synergistic effects of identified drugs with efflux pump inhibitors.

Main Methods:

• A three-step workflow: target screening (CEG 2.0), drug screening (DrugBank, antiBac-Pred, molecular docking, molecular dynamics [MD] simulation), and in vitro antibacterial assays.
• Utilized MD simulations to confirm drug-target binding stability.

Main Results:

• Identified daprodustat and ezetimibe as effective against Staphylococcus aureus and Escherichia coli ΔtolC by targeting the bacterial chaperone GroEL.
• Observed synergistic antibacterial effects when daprodustat was combined with the efflux pump inhibitor PAβN against both bacterial species.
• Ezetimibe showed potentiated efficacy against S. aureus when combined with PAβN.
• MD simulations confirmed stable binding of daprodustat and ezetimibe to bacterial GroEL.

Conclusions:

• Validated a computational workflow for effective drug repurposing against bacterial infections.
• Demonstrated the feasibility of computer-aided drug repurposing for discovering novel therapeutics for various diseases.
• Highlighted the promising synergistic potential of combining daprodustat with efflux pump inhibitors as a broad-spectrum antibacterial strategy.