Peptide‐induced inhibition of ATP Synthase as an alternative approach to combat microbial infections

Background ATP synthase is the fundamental means of cellular energy production. Inhibition of ATP synthase can deprive cell of required energy resulting in cell death. A wide variety of cationic α‐helical peptides are known to bind and inhibit ATP synthase. Our lab has studied the inhibitory effects of a variety of peptides with anti‐microbial and anti‐tumor properties on Escherichia coli ATP synthase. Peptide‐induced inhibition of E. coli ATP synthase establishes that the anti‐microbial and anti‐tumor effects of peptides are at least in part linked to the blocking of ATP synthesis in tumor and bacterial cells. Method Wild‐type E. coli strain, pBWU13.4 growth properties were checked on fermentable glucose and non‐fermentable succinate carbon sources before harvesting cells in minimal media to isolate ATP synthase. Peptide‐induced inhibitory studies were performed on membrane bound F 1 F o ATP synthase. An additional positive charge in the form of a c‐terminal NH 2 group was added to augment the extent of inhibition. Abrogation of cell growth was tested in presence and absence of peptides along with null control pUC118 strain. Results Peptides caused variable degree of inhibition. Potency of inhibition was found to be related to the complexity and number of positively charged residues. It was observed that the presence of a c‐terminal NH 2 group on the peptides enhances the inhibitory potency on molar scale. Our studies also demonstrated that peptides follow a differential pattern of inhibition. These results confirm that incremental addition of positively charged residues can augment the inhibitory effects of peptides by about 100‐fold. Moreover, growth of wild‐type E. coli was fully abrogated while no effect was observed on the growth of null cells in presence of peptides. Thus, making ATP synthase a potent molecular drug target for anti‐microbial and anti‐tumor peptides. Currently, we are studying the inhibitory effects of venom peptides from different sources along with synergetic inhibitory effects of peptides on ATP synthase. Conclusions We conclude that cationic α‐helical peptides are potent inhibitors of E. coli ATP synthase. Our data suggests that the inhibitory potency of peptides can be enhanced by inserting additional positive charges including c‐terminal amide group. Finally, the selective inhibition of bacterial ATP synthase is an alternative novel approach to comate microbial infections. Support or Funding Information National Institutes of Health Grant GM085771