Repurposing Metronidazole Derivatives to Target Aerobic Bacteria via FabH Inhibition

What is it about?

For more than 60 years, metronidazole has served as an antibacterial and antiprotozoal agent. But its use has been limited to anaerobic microorganisms and is usually not effective on Gram-negative and Gram-positive facultative anaerobic bacteria, which are considered as the most life-threatening pathogens. The canonical mechanism of action of metronidazole is thought to be reductive bioactivation of the nitro group by electron-transport system of anaerobic microorganisms which is sufficiently negative to reduce nitro group. This resulting in the generation of radicals and other reactive intermediates such as nitroso and hydroxylamine, and then the radicals and toxic reactive intermediates interact with microbial DNA to exert their bactericidal effect. Recent studies demonstrated that metronidazole analogues can have potent activity against the facultative anaerobic bacteria suggesting there is different mode of action of metronidazole. Previous research has shown that several newly developed compounds can effectively inhibit a key enzyme β-ketoacyl-acyl carrier protein synthase III (FabH), which is re-sponsible for initiating the fatty acid biosynthesis pathway (FAB). In addition, a study of the crystal structure of E. coli FabH complexed with various ligands provided evidence that acetyl-CoA is a preferred substrate at the active site of FabH Therefore, we have proposed that incorporating an acetyl group into metronidazole analogs might lead to additional interactions at the binding site of FabH.

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Photo by National Institute of Allergy and Infectious Diseases on Unsplash

Photo by National Institute of Allergy and Infectious Diseases on Unsplash

Why is it important?

In this research work we have demonstrated that the synthetic derivatives of metronidazole possess antibacterial activity against facultative anaerobic bacteria. Further acetylation of 2-styryl-5-nitroimidazoles not only improved the biological activity but also enhanced the binding interaction of the drug in the active site of target protein FabH.