Development of Quorum Sensing Modulators of Streptococcus constellatus

Streptococcus constellatus inhabits the healthy human gastrointestinal tract and oral microbiome; however, the incidence of this species becoming opportunistically pathogenic has increased in recent decades. S. constellatus has the potential to cause severe pyogenic infections requiring combination antibiotic therapy or surgical intervention. Some virulence processes in S. constellatus , such as genetic competence, are regulated through quorum sensing (QS), facilitated by its 16‐mer competence stimulating peptide (CSP). Several target residues on the CSP molecule were identified that can be mutated to enhance the peptide activity and/or lead to competitive inhibition of the competence regulon QS circuitry, thereby modulating related pathogenic phenotypes. Using a rational design approach, second‐generation peptide analog libraries were designed and screened, resulting in optimization of a competitive QS inhibitor, CSP‐D1AI4AM6A, with an IC ₅₀ of 38.3 nM. Overall, this work provides a rational framework upon which novel QS modulators can be designed to attenuate virulence processes in this opportunistic pathogen.