ATP synthase: A potential molecular drug target

Background According to the Review on Antimicrobial Resistance, antibiotic resistance will result in 10 million additional deaths worldwide per year by 2050 surpassing cancer. Fast‐encroaching antibiotic resistance by microbes in general and E. coli in particular is the main reason for this situation. Thus, finding alternative ways to kill microbes is of paramount importance. ATP synthase is the principal source of cellular energy in almost all organisms. Selective inhibition of microbial ATP synthase may deprive microbes of required energy leading to cell death. A wide variety of inhibitors including phytochemicals and peptides bind and inhibit ATP synthase. These phytochemicals and peptides bind to the explicit binding sites on ATP synthase. Although binding sites are highly conserved, they are flanked by variable amino acids, which participate in selective binding of inhibitors. Our lab is interested in identifying the selective inhibitors of ATP synthase using Escherichia coli as a model organism. Method Wild type, null, and mutant E. coli strains are used to select the potent inhibitors of ATP synthase. Growth of E. coli strains is measured on fermentable and non‐fermentable carbon sources. Membrane bound F 1 F o ATP synthase is isolated by harvesting cells in the minimal media, breaking cells by French Press, and separating the enzyme by multiple high‐speed ultracentrifugation. A variety of phytochemical and peptide inhibitors are used to inhibit membrane bound ATP synthase. Inhibitory potency of inhibitors is amplified through addition or subtraction of functional groups. Results Natural inhibitors caused variable degree of inhibition. Structural modifications resulted in augmented inhibition. Re‐positioning of −OH, NH 2 , PO 4 groups in phytochemicals or addition of a c‐terminal NH 2 group in peptides augmented the inhibitory effects by about 100‐fold. Phytochemicals and peptides also showed synergistic inhibitory effects on ATP synthase. Conclusions Phytochemicals and peptides potently kill E. coli cells by binding at the F 1 sector of ATP synthase. Thus, ATP synthase can be used as a potent molecular drug target to combat antibiotic resistant microbial infections. Support or Funding Information A.T. Still University Warner/Fermaturo Research Grant, grant 501–605 to ZA. This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal .