Role of ATP synthase as a molecular drug target against bacterial infections

Abstract

BackgroundF1Fo ATP synthase is the main source of cellular energy in almost all organisms from bacteria to man through oxidative phosphorylation. Binding of ADP and Pi in the catalytic sites of ATP synthase is essential for the formation of ATP. Inhibition of ATP synthase deprives cells of required energy in the form of ATP resulting in cell death. Here, we propose that ATP synthase can be used as a molecular drug target against microbial infections in general and bacterial infections in particular. This can be achieved by targeting the bacterial ATP synthase. A wide variety of phytochemicals and peptides are known to potently in inhibit the ATP synthase. Thus, identification of natural phytochemicals or antibacterial peptides is an important goal towards using ATP synthase as a molecular drug target.MethodsPhytochemicals or peptide induced inhibition of wild type purified F1 or membrane bound F1Fo ATP synthase were performed. Many polyphenolic compounds were structurally modified to increase the extent of inhibition and potency on molar scale. Mutagenic analysis of polyphenol binding and peptide binding site was done to understand the mechanism of inhibition. Growth yield in limiting glucose and non‐fermentable carbon source succinate in presence or absence of inhibitors was done to prove the ATP synthase related cell death.ResultsLately, we found that structural medication of polyphenolic compound such as resveratrol resulted in ~60% additional inhibition of ATP synthase and caused complete abrogation of wild type E. coli cells while mutant cells along with null cells were not affected. Currently, we are studying the role of βDELSEED‐motif in peptide binding to elucidate the mechanism of inhibition of ATP synthase.