Strong inhibitory effects of curcumin and its demethoxy analog on Escherichia coli ATP synthase F1 sector

International Journal of Biological Macromolecules

2017

The naturally occurring olive phenolics tyrosol, hydroxytyrosol, dihydroxyphenylglycol (DHPG), and oleuropein are known to have antioxidant, antitumor, and antibacterial properties. In the current study, we examined whether the antimicrobial properties of tyrosol, hydroxytyrosol, DHPG, and oleuropein were linked to the inhibition of bacterial ATP synthase. Tyrosol, hydroxytyrosol, DHPG, and oleuropein inhibited Escherichia coli wild-type and mutant membrane-bound F1Fo ATP synthase to variable degrees. The growth properties of wild-type, null, and mutant strains in presence of above olive phenolics were also abrogated to variable degrees on limiting glucose and succinate. Tyrosol and oleuropein synergistically inhibited the wild-type enzyme. Comparative wild-type and mutant F1Fo ATP synthase inhibitory profiles suggested that αArg-283 is an important residue and olive phenolics bind at the polyphenol binding pocket of ATP synthase. Growth patterns of wild-type, null, and mutant strains in the presence of tyrosol, hydroxytyrosol, DHPG, and oleuropein also hint at the possibility of additional molecular targets. Our results demonstrated that ATP synthase can be used as a molecular target and the antimicrobial properties of olive phenolics in general and tyrosol in particular can be linked to the binding and inhibition of bacterial ATP synthase.

Section: Discussionmentioning

confidence: 51%

Understanding the link between antimicrobial properties of dietary olive phenolics and bacterial ATP synthase

Amini

Liu

International Journal of Biological Macromolecules

2017

“…Partial or complete inhibition of ATPase has also been observed in the presence of natural or structurally modified polyphenol compounds. Similar inhibition of ATPase activity has also been linked to the reduced growth of bacterial or tumor cells [61–63, 69, 70]. …”

Section: Discussionmentioning

confidence: 85%

Asp residues of βDELSEED-motif are required for peptide binding in the Escherichia coli ATP synthase

International Journal of Biological Macromolecules

Tayou

Laughlin

2015

This study demonstrates the requirement of Asp-380 and Asp-386 in the βDELSEED-motif of E. coli ATP synthase for peptide binding and inhibition. We studied the inhibition profiles of wild-type and mutant E. coli ATP synthase in presence of c-terminal amide bound melittin and melittin related peptide. Melittin and melittin related peptide inhibited wild-type ATPase almost completely while only partial inhibition was observed in single mutations with replacement of Asp to Ala, Gln, or Arg. Additionally, very little or no inhibition occurred among double mutants βD380A/βD386A, βD380Q/βD386Q, or βD380R/βD386R signifying that removal of one Asp residue allows limited peptide binding. Partial or substantial loss of oxidative phosphorylation among double mutants demonstrates the functional requirement of βD380 and βD386 Asp residues. Moreover, abrogation of wild-type E. coli cell growth and normal growth of mutant cells in presence of peptides provides strong evidence for the requirement of βDELSEED-motif Asp residues for peptide binding. It is concluded that while presence of one Asp residue may allow partial peptide binding, both Asp residues, βD380 and βD386, are essential for proper peptide binding and inhibition of ATP synthase.

“…The interaction between the majority of these inhibitors and ATP synthase residues and the specific sites remains unknown [ 10 , 20 , 80 ]. The two therapeutically important antimicrobial ATP synthase inhibitors are antimicrobial peptides, which mainly bind at the peptide-binding pocket formed by the βDELSEED-motif [ 13 , 81 - 88 ], and antimicrobial phytochemicals, which mainly bind at the phytochemical or polyphenol binding pocket contributed by α-, β-, and, γ-subunit residues [ 10 - 12 , 21 - 24 , 80 , 88 - 103 ]. Selective inhibition of F 1 F o ATP synthase is a promising way to deal with multiple disease conditions, including antibiotic-resistant microbial infections.…”

Section: Atp Synthase Inhibitorsmentioning

confidence: 99%

A Therapeutic Connection between Dietary Phytochemicals and ATP Synthase

Hassan²,

Azim

2017

CMC

For centuries, phytochemicals have been used to prevent and cure multiple health ailments. Phytochemicals have been reported to have antioxidant, antidiabetic, antitussive, antiparasitic, anticancer, and antimicrobial properties. Generally, the therapeutic use of phy-tochemicals is based on tradition or word of mouth with few evidence-based studies. Moreo-ver, molecular level interactions or molecular targets for the majority of phytochemicals are unknown. In recent years, antibiotic resistance by microbes has become a major healthcare concern. As such, the use of phytochemicals with antimicrobial properties has become perti-nent. Natural compounds from plants, vegetables, herbs, and spices with strong antimicrobial properties present an excellent opportunity for preventing and combating antibiotic resistant microbial infections. ATP synthase is the fundamental means of cellular energy. Inhibition of ATP synthase may deprive cells of required energy leading to cell death, and a variety of die-tary phytochemicals are known to inhibit ATP synthase. Structural modifications of phyto-chemicals have been shown to increase the inhibitory potency and extent of inhibition. Site-directed mutagenic analysis has elucidated the binding site(s) for some phytochemicals on ATP synthase. Amino acid variations in and around the phytochemical binding sites can re-sult in selective binding and inhibition of microbial ATP synthase. In this review, the therapeu-tic connection between dietary phytochemicals and ATP synthase is summarized based on the inhibition of ATP synthase by dietary phytochemicals. Research suggests selective target-ing of ATP synthase is a valuable alternative molecular level approach to combat antibiotic resistant microbial infections.