Melatonin inhibits Gram-negative pathogens by targeting citrate synthase

Area of Science:

• Microbiology
• Infectious Diseases
• Drug Discovery

Background:

• Gram-negative bacterial infections pose a significant global health challenge.
• There is an urgent need for novel antibiotics due to limited development pipelines.
• Repurposing existing compounds is a viable strategy for new antibiotic development.

Purpose of the Study:

• To investigate the efficacy of melatonin as a potential therapeutic agent against Gram-negative bacterial infections.
• To elucidate the mechanism by which melatonin exerts its antibacterial effects.

Main Methods:

• Mice models were used to assess survival rates and bacterial loads during infection.
• In vitro assays were performed to determine the inhibitory effect of melatonin on bacterial citrate synthase.
• Molecular docking was employed to identify binding sites of melatonin on citrate synthase.

Main Results:

• Melatonin significantly improved survival rates and reduced lung bacterial loads in infected mice.
• Melatonin was found to specifically inhibit the activity of citrate synthase in Gram-negative pathogens.
• Melatonin directly binds to key sites (R300, D363, H265) of citrate synthase, notably in Pasteurella multocida.

Conclusions:

• Melatonin demonstrates potential as an alternative therapy against Gram-negative infections.
• Inhibition of bacterial citrate synthase by melatonin disrupts essential metabolic pathways.
• Repurposing melatonin offers a promising strategy to combat the growing threat of antibiotic resistance.