Biological evaluation of native streptococcal competence stimulating peptides reveals potential crosstalk between Streptococcus mitis and Streptococcus pneumoniae and a new scaffold for the development of S. pneumoniae quorum sensing modulators

Streptococcus pneumoniae, an opportunistic human pathogen, acquires genes from its neighboring species of the mitis group of streptococci, which confer antibiotic resistances and allow it to produce diverse virulence factors. Most species of the mitis group are naturally competent, and they utilize the competence stimulating peptide (CSP) and the CSP-dependent competence regulon, a conserved quorum sensing (QS) circuit, to regulate their competence behavior. The dependence of the mitis group on this communication pathway makes QS a potential target to control their behavior. In this work, we sought to evaluate the impact of the native pheromones of the adjacent species of S. pneumoniae to modulate the activity of the S. pneumoniae competence regulon. Our results revealed the potential role of S. mitis as a modulator of QS in S. pneumoniae. Most importantly, our analysis also revealed that by using the native pheromone of S. mitis as a template, highly potent pan-group agonists and antagonists of the pneumococcal competence regulon could be developed. The newly developed QS modulators may have therapeutic utility in treating pneumococcal infections.