Antibiotic-induced cell chaining triggers pneumococcal competence by reshaping quorum sensing to autocrine signaling

Streptococcus pneumoniae can acquire antibiotic resistance by activation of competence and subsequent DNA uptake. Several antibiotics induce competence by disrupting protein-quality control or perturbing DNA replication. Here, we demonstrate that aztreonam (AZT) and clavulanic acid (CLA) also promote competence. We show that both compounds induce cell chain formation by targeting the D,D-carboxypeptidase PBP3. In support of the hypothesis that chain formation promotes competence, we demonstrate that an autolysin mutant ( lytB ) is hypercompetent. As competence is initiated by the binding of a small extracellular peptide (CSP) to a membrane-anchored receptor (ComD), we wondered if chain formation alters CSP diffusion and thereby sensing by ComD. Indeed, the presence of AZT or CLA affects competence synchronization by switching CSP-based quorum sensing to autocrine-like signaling, as CSP is retained to chained cells and no longer shared in a common pool. Together, these insights demonstrate the versatility of quorum sensing in integrating different stresses and highlight that certain antibiotics should be prescribed with care not to drive the spread of antibiotic resistance.