Development of antipathogenic agents targeting biosynthetic enzyme and receptor of cyclic peptide quormone

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Quorum sensing with thiolactone or lactone peptide as an autoinducer is common among a number of Gram-positive bacteria and controls the expression of virulence in some pathogens, e. g., staphylococci, enterococci and listeria. In this context, the validity of anti-pathogenic agents targeting this type of quorum sensing has been proposed. In this study, to aim inhibitors targeting the cyclic peptide-mediated quorum sensing in Gram-positive bacteria, we have been employing two approaches, that are random screening of microbial secondary metabolites and drug design of peptide antagonists. For the screening, we have established an efficient screening system using an gelatinase assay of Enterococcus faecalis. Thus far, we have tested more than a thousand extracts of fungi and actinomycetes and more than a hundred natural and synthetic compounds and found several compounds to efficiently inhibit either or both staphylococci agr and enterococci fsr quorum sensing systems. For the design of p … More eptide antagonist, we took our original approach, called reverse alanine scanning, during which more potent antagonists were led step by step from receptor-binding scaffold that is[ Ala4, 5, 6, 8, 9, 11]] Z-GBAP(GBAP is an autoinducing lactone peptide of E. faecalis fsr system). In consequence, 5th, 9th and 11th residues in GBAP were found to be antagonist pharmacophore and with this information, we have eventually created a potent antagonist, named ZBzl-YAA5911(IC80=0. 1μM). To elucidate the availability of ZBzl-YAA5911 as an anti-infective agent, the efficacy of this peptide for endophthalmitis was assessed with an aphakic rabbit endophthalmitis model. As a result, ZBzl-YAA5911 suppressed the translocation of E. faecalis from the aqueous humor into the vitreous cavity more than one order magnitude and also significantly reduced the retinal damage of animals, suggesting that ZBzi-YAA5911 would be useful as anti-pathogenic agent to attenuate virulence expression more than eliminate the opportunistic pathogen. Less