Designing Highly Potent Side-Chain Lactam-Bridged\nCyclic Competence-Stimulating Peptide-Based Quorum-Sensing Modulators\nin Streptococcus oligofermentans

Streptococcus oligofermentans, a\nGram-positive bacterium found in the oral microbiome, shows promise\nas an oral probiotic for preventing dental caries. It exhibits a reverse\ncorrelation with Streptococcus mutans, a key caries-causing pathogen, likely due to its production of\nhydrogen peroxide, a process mediated by quorum sensing (QS). In this\nwork, we set out to develop novel lactam-based cyclic analogues of\nthe competence stimulating peptide (CSP) signal utilized by S. oligofermentans for QS activation. To this end,\nwe first conducted a ring position scan, where we determined the best\npositions within the CSP sequence to use for macrolactamization. We\nthen conducted systematic ring size and bridge position scans to fine-tune\nthe cyclic peptide conformation and identified a cyclic analogue,\nCSP-cyc(K2E2), with enhanced biological activity, 7-fold more active\nthan the native CSP signal. This analogue also exhibited improved\nstability toward enzymatic degradation, demonstrating this analogue’s\npotential utility as a chemical probe to study interspecies interactions\nbetween oral microbes and as a potential therapeutic agent. Overall,\nour lead cyclic analogue could be applied to augment the biotherapeutic\npotential of S. oligofermentans against S. mutans infections.