Repurposing celecoxib analogues as leads for antibiotics

Area of Science:

• Microbiology
• Medicinal Chemistry
• Drug Discovery

Background:

• Antibiotic resistance is a growing global health threat, necessitating the development of novel antimicrobial agents.
• Existing treatments are becoming less effective against multidrug-resistant bacterial strains, including methicillin-resistant Staphylococcus aureus (MRSA) and Acinetobacter baumannii.
• There is an urgent need for innovative strategies and new drug candidates to overcome bacterial pathogens.

Purpose of the Study:

• To evaluate the potential of a novel compound (Compound 12) as an antibacterial agent.
• To assess the antimicrobial efficacy, mechanism of action, and in vivo effectiveness of Compound 12.
• To explore Compound 12 as a candidate for further development in combating bacterial infections.

Main Methods:

• Molecular docking simulations were employed to predict interactions with bacterial targets.
• In vitro antibacterial activity was determined using minimum inhibitory concentration (MIC) assays against Staphylococcus aureus, MRSA, and Acinetobacter baumannii.
• In vivo efficacy was assessed in a mouse model of MRSA infection, alongside cytotoxicity and enzyme inhibition analyses (dihydrofolate reductase and DNA gyrase).

Main Results:

• Compound 12 displayed potent antimicrobial activity against Staphylococcus aureus (MIC: 4 μg/ml), MRSA strains (MIC: 4-16 μg/ml), and Acinetobacter baumannii (MIC: 4 μg/ml), particularly when potentiated by colistin B.
• In vivo studies showed Compound 12 (20 mg/kg) offered a mild survival benefit in MRSA-infected mice.
• Enzyme inhibition assays revealed Compound 12 targets S. aureus dihydrofolate reductase (105.1 μg/ml) and DNA gyrase (122.8 μg/ml).

Conclusions:

• Compound 12 exhibits promising broad-spectrum antibacterial properties against key pathogens.
• The compound's ability to inhibit essential bacterial enzymes suggests a viable mechanism of action.
• Compound 12 represents a potential lead candidate for the development of new antibiotics to address the challenge of antimicrobial resistance.