biostudies-literatureGuo MNational Institutes of HealthUniversity of Nevada, RenoNational Institute of General Medical SciencesNIGMS NIH HHS298-311.e6https://www.ebi.ac.uk/biostudies/studies/S-EPMC10922391biostudies-literatureUnknown31(2)Natural competence is the principal driver of streptococcal evolution. While acquisition of new traits could facilitate rapid fitness improvement for bacteria, entry into the competent state is a highly orchestrated event, involving an interplay between various pathways. We present a new type of competence-predation coordination mechanism in Streptococcus sanguinis. Unlike other streptococci that mediate competence through the ComABCDE regulon, several key components are missing in the S. sanguinis ComCDE circuitry. We assembled two synthetic biology devices linking competence-stimulating peptide (CSP) cleavage and export with a quantifiable readout to unravel the unique features of the S. sanguinis circuitry. Our results revealed the ComC precursor cleavage pattern and the two host ABC transporters implicated in the export of the S. sanguinis CSP. Moreover, we discovered a ComCDE-dependent bacteriocin locus. Overall, this study presents a mechanism for commensal streptococci to maximize transformation outcome in a fluid environment through extensive circuitry rewiring.Cell chemical biologyNoncanonical Streptococcus sanguinis ComCDE circuitry integrates environmental cues in transformation outcome decision.PMC10922391R35 GM128651R35GM128651P30 103650Guo MMull RWTal-Gan YRenshaw CPfalseNoncanonical Streptococcus sanguinis ComCDE circuitry integrates environmental cues in transformation outcome decision.Natural competence is the principal driver of streptococcal evolution. While acquisition of new traits could facilitate rapid fitness improvement for bacteria, entry into the competent state is a highly orchestrated event, involving an interplay between various pathways. We present a new type of competence-predation coordination mechanism in Streptococcus sanguinis. Unlike other streptococci that mediate competence through the ComABCDE regulon, several key components are missing in the S. sanguinis ComCDE circuitry. We assembled two synthetic biology devices linking competence-stimulating peptide (CSP) cleavage and export with a quantifiable readout to unravel the unique features of the S. sanguinis circuitry. Our results revealed the ComC precursor cleavage pattern and the two host ABC transporters implicated in the export of the S. sanguinis CSP. Moreover, we discovered a ComCDE-dependent bacteriocin locus. Overall, this study presents a mechanism for commensal streptococci to maximize transformation outcome in a fluid environment through extensive circuitry rewiring.2024-01-01T00:00:00Z2024 Feb2026-06-02T04:10:12.476Z2025-04-19T13:44:11.305ZS-EPMC109223913783255110.1016/j.chembiol.2023.09.007