Self-immunity towards a novel competence-induced streptococcal murein hydrolase is mediated by a Fem-transferase-like protein

Murein hydrolases (or peptidoglycan hydrolases) play diverse roles in bacteria, from controlled remodeling of the bacterial cell wall to lytic agents. In streptococci, a subset of these hydrolases is associated with competence-induced fratricide, a process where bacteria kill closely related cells to release DNA that can be taken up during natural transformation. Here, we characterize ScrM, a competence-induced murein hydrolase from Streptococcus dysgalactiae comprising a CHAP domain, an SH3b domain and an uncharacterized C-terminal domain (CCD). ScrM displayed lytic activity against pyogenic and salivarius group streptococci. Microscopy analysis of fluorescent fusions revealed that ScrM specifically localizes to the division zone of sensitive cells, with binding and localization mediated primarily by CCD. Upon competence induction, cells became immune to ScrM due to expression of ScrI, a Fem-transferase-like protein. We show by LC-MS/MS that ScrI incorporates Thr in place of Ala into the interpeptide bridges of peptidoglycan, which in turn prevents ScrM binding to the division zone, thereby protecting the cells from self-lysis during competence. ScrM and ScrI are conserved among pyogenic streptococcal pathogens and represent new players in the cell wall biogenesis of these bacteria that may form a platform for development of novel antimicrobial strategies.