Selective inhibition ATP Synthase in combating microbial infections

Abstract

BackgroundATP synthase is main source of cellular energy for almost all organisms. Malfunction or inhibition of ATP synthase may cause cell death. A wide variety of inhibitors including phytochemicals and peptides are known to bind and inhibit ATP synthase. These phytochemicals and peptides bind to the specific binding pockets on ATP synthase. These binding pockets are flanked by variable amino acids in different species. Our lab is exploring the possibility of using ATP synthase as a selective molecular drug target to combat the antibiotic resistant microbial infections using Escherichia coli as a model organism.MethodWild type, null, and mutant E. coli growth properties were tested on fermentable glucose and non‐fermentable succinate carbon sources. Wild type and mutant enzymes were isolated by harvesting cells in the minimal media. Inhibitory studies were performed on membrane bound F1Fo ATP synthase. Structural modifications of inhibitors were made through replacement or re‐positioning of the functional groups on phytochemicals or addition of positive charges on the peptides. Wild type and mutant cell growth assays were tested in presence and absence of inhibitors along with null control.ResultsPhytochemicals and peptides caused variable degree of inhibition. Extent of inhibition was augmented by modification of inhibitors. For phytochemicals, re‐positioning and addition of new functional groups and for peptides, addition of a c‐terminal NH2 group enhanced the inhibitory potency on molar scale. We also found that incremental addition of positively charged residues in peptides can augment the inhibitory effects of peptides by about 100‐fold. Cell growth assays in presence and absence inhibitors suggest that ATP synthase is a potent molecular drug target to combat microbial infections. Currently, we are studying the synergistic inhibitory effects of phytochemicals and peptides on ATP synthase.ConclusionsWe conclude that phytochemicals and peptides bind and inhibit E. coli by interacting at the specific sites on F1 sector of ATP synthase and ATP synthase is a potential molecular drug target.Support or Funding InformationKCOM‐ATSU Biomedical Sciences Graduate Program Grant Award # 850‐611, 850‐619, and 851‐026This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.