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Development and validation of thiolactone peptide mimics to antagonize agr-quorum sensing system in Staphylococcus aureus

S.Adline Princy, T.Naveen Kumar, V.Praveen Krishna, D.Bharath, R.Vinoth Kannan

Staphylococcus aureus variants evolved via a group specific/ non-group specific interaction of a two component system, histidine-kinase receptor, AgrC and autoinducing peptide, AIP. In consistent to this report, our prime interest was to develop and validate a global inhibitor against these variants using peptidomimetic approach.As one of theAIP variant (AIPII) also reported to show weak activator of its own and cross inhibitor of the others, its response domain (macrocyclic ring)was theoretically substituted with the aminoacids (glycine, phenylalanine, isoleucine, tyrosine) that had earlier showed significant in inhibiting virulence effect of S.aureuskeeping constant the conserved residue, cysteine. The AIP-II mimics, mAIP-II [1] and mAIP-II [2] that showed the best glide score on docking with the protein AgrC variants individually were synthesized to confirmits biological competitivemode of action in the presence of 100nM of naturalAIP of its respective groups using reporter strains. The mAIPII[ 1] was further validated in invivo rat protection test and the histopathological studies showed the infiltration of neutrophils in the infected region among diseased groups, where in treated groups the region consists of predominantly lymphocytes and angiogenesis, a clear confirmation of healing process. Thus we conclude the peptidomimetic approach would be a promising approach to design a global inhibitor to inhibit virulence genes among S.aureus variants.