A target-guided drug repurposing strategy for antibacterial discovery

Area of Science:

• Microbiology
• Computational Chemistry
• Drug Discovery

Background:

• Rising antibiotic resistance necessitates novel antibacterial development strategies.
• Drug repurposing (DR) presents a viable approach to accelerate the discovery of new antibacterial agents.
• This study validates a DR-based strategy for identifying novel antibacterials against resistant pathogens.

Purpose of the Study:

• To computationally screen a large library of approved non-antibacterial drugs for potential antibacterial activity.
• To experimentally validate the antibacterial efficacy of candidate drugs identified through molecular docking.
• To elucidate the mechanism of action for promising repurposed drugs.

Main Methods:

• Molecular docking of 2,027 approved drugs against 125 essential bacterial proteins using Vina-GPU.
• In vitro screening of 14 candidate drugs against six Gram-negative bacterial strains.
• Assays with Polymyxin B nonapeptide (PMBN) and optical density measurements to determine inhibition rates.
• Mechanism validation using Surface Plasmon Resonance (SPR), Molecular Dynamics (MD) simulations, and folate rescue experiments.

Main Results:

• Several non-antibacterial drugs demonstrated significant antibacterial activity in preliminary screening.
• Molecular docking identified potential drug-target interactions for antibacterial efficacy.
• Multiple repurposed drugs exhibited broad-spectrum activity against various bacterial species.
• The combination of lifitegrast and PMBN effectively inhibited six Gram-negative bacteria.

Conclusions:

• Lifitegrast, in combination with PMBN, shows potent inhibitory effects against six Gram-negative bacterial strains.
• Preliminary evidence suggests lifitegrast functions by inhibiting FolA, a key enzyme in folate metabolism.
• Further investigation into the structure-activity relationship of lifitegrast is warranted to optimize its antibacterial potential.