Development of a peptide antagonist against fsr quorum sensing of enterococcus faecalis

Jiro Nakayama, Ryoji Yokohata, Mami Sato, Takashi Suzuki, Takahisa Matsufuji, Kenzo Nishiguchi, Takeshi Kawai, Yosuke Yamanaka, Koji Nagata, Masaru Tanokura, Kenji Sonomoto

Research output: Contribution to journalArticle

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Abstract

Enterococcus faecalis fsr quorum sensing (QS) involves an 11-residue cyclic peptide named gelatinase biosynthesis-Activating pheromone (GBAP) that autoinduces two pathogenicity-related extracellular proteases in a cell density-dependent fashion. To identify anti-pathogenic agents that target fsr QS signaling, peptide antagonists of GBAP were created by our unique drug design approach based on reverse alanine scanning. First of all, a receptor-binding scaffold (RBS), [Ala4,5,6,8,9,11]Z-GBAP, was created, in which all amino acids within the ring region of GBAP, except for two essential aromatic residues, were substituted to alanine. Next, the substituted alanine residues were changed back to the original amino acid one by one, permitting selection of those peptide combinations exhibiting increased antagonist activity. After three cycles of this reverse alanine scan, [Ala5,9,11]Z-GBAP was obtained as a maximally reverted peptide (MRP) holding the strongest antagonist activity. Then, the fifth residue in MRP, which is one of the critical residues to determine agonist/antagonist activity, was further modified by substituting with different types of amino acids including unnatural amino acids. As a result, [Tyr(Bzl)5, Ala9,11]Z-GBAP, named ZBzl-YAA5911, showed the strongest antagonist activity [IC50 = 26.2 nM and K d against GBAP receptor (FsrC) = 39.4 nM]. In vivo efficacy of this peptide was assessed with an aphakic rabbit endophthalmitis model. ZBzl-YAA5911 suppressed the translocation of E. faecalis from the aqueous humor into the vitreous cavity by more than 1 order of magnitude and significantly reduced retinal damage. We propose that ZBzl-YAA5911 or its derivatives would be useful as anti-infective agents to attenuate virulence expression in this opportunistic pathogen.

Original languageEnglish
Pages (from-to)804-811
Number of pages8
JournalACS Chemical Biology
Volume8
Issue number4
DOIs
Publication statusPublished - Apr 19 2013

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Quorum Sensing
Enterococcus faecalis
Peptides
Alanine
Amino Acids
Virulence
Pheromone Receptors
Cyclic Peptides
Endophthalmitis
Aqueous Humor
Drug Design
Pathogens
Anti-Infective Agents
gelatinase biosynthesis-activating pheromone
Scaffolds
Inhibitory Concentration 50
Peptide Hydrolases
Cell Count
Rabbits
Derivatives

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Molecular Medicine

Cite this

Nakayama, J., Yokohata, R., Sato, M., Suzuki, T., Matsufuji, T., Nishiguchi, K., ... Sonomoto, K. (2013). Development of a peptide antagonist against fsr quorum sensing of enterococcus faecalis. ACS Chemical Biology, 8(4), 804-811. https://doi.org/10.1021/cb300717f

Development of a peptide antagonist against fsr quorum sensing of enterococcus faecalis. / Nakayama, Jiro; Yokohata, Ryoji; Sato, Mami; Suzuki, Takashi; Matsufuji, Takahisa; Nishiguchi, Kenzo; Kawai, Takeshi; Yamanaka, Yosuke; Nagata, Koji; Tanokura, Masaru; Sonomoto, Kenji.

In: ACS Chemical Biology, Vol. 8, No. 4, 19.04.2013, p. 804-811.

Research output: Contribution to journalArticle

Nakayama, J, Yokohata, R, Sato, M, Suzuki, T, Matsufuji, T, Nishiguchi, K, Kawai, T, Yamanaka, Y, Nagata, K, Tanokura, M & Sonomoto, K 2013, 'Development of a peptide antagonist against fsr quorum sensing of enterococcus faecalis', ACS Chemical Biology, vol. 8, no. 4, pp. 804-811. https://doi.org/10.1021/cb300717f
Nakayama, Jiro ; Yokohata, Ryoji ; Sato, Mami ; Suzuki, Takashi ; Matsufuji, Takahisa ; Nishiguchi, Kenzo ; Kawai, Takeshi ; Yamanaka, Yosuke ; Nagata, Koji ; Tanokura, Masaru ; Sonomoto, Kenji. / Development of a peptide antagonist against fsr quorum sensing of enterococcus faecalis. In: ACS Chemical Biology. 2013 ; Vol. 8, No. 4. pp. 804-811.
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