Dataset Information

Streptococcal S protein is a coordinator of cell wall repair and defense against host antimicrobials

ABSTRACT: Pathogenic bacteria have acquired the ability to resist antibacterial defense mechanisms of the host. Streptococci are common in animal microbiota and include opportunistic pathogens like Group A Streptococcus (GAS) and Streptococcus pneumoniae (pneumococcus). While the conserved streptococcal S protein has been identified as a key factor in GAS virulence, its exact function is unclear. Here, we show that the pneumococcal S protein is crucial for resisting against host-derived antimicrobials by coordinating cell wall modification and repair. Specifically, we show that S proteins are septally localized through their transmembrane domain and contain an extracellular peptidoglycan (PG) binding LysM domain which is required for its function. Protein-protein and genetic interaction studies demonstrate that the pneumococcal S protein directly interacts with a PG synthase, class A penicillin binding protein PBP1a, and the PG deacetylase PgdA. Single molecule experiments reveal that the fraction of circumferentially moving PBP1a molecules is reduced in the absence of S protein. Consistent with an impaired PBP1a function, streptococci lacking S protein exhibit increased susceptibility to cell wall targeting antibiotics and altered cell morphologies. PG analysis showed reduced N-deacetylation of glycans in the S. pneumoniae S protein mutant, indicating reduced PgdA activity. We show that pneumococci lacking the S protein cannot persist transient penicillin treatment, are more susceptible to the human antimicrobial peptide LL-37 and to lysozyme, and show decreased virulence in zebrafish and mice. Our data support a model in which S proteins activate regulate PBP1a activity and play a key role in coordinating PG repair and modification. This cell wall ‘sentinel’ control system provides defense against host-derived and environmental antimicrobial attack.

INSTRUMENT(S):

ORGANISM(S): Streptococcus Pneumoniae Serotype 2 (strain D39 / Nctc 7466)

SUBMITTER: Jan-Willem Veening

LAB HEAD: Jan-Willem Veening

PROVIDER: PXD055534 | Pride | 2026-06-08

REPOSITORIES: Pride

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Pneumococcal S protein coordinates cell wall modification and repair to resist host antimicrobials.

Burnier Jessica J Gallay Clement C Bruce Kevin E KE Bjånes Elisabet E Martin Louise L Jim Kin Ki KK Tsui Ho-Ching Tiffany HT Cremers Amelieke J H AJH Mignolet Johann J Vollmer Daniela D Biboy Jacob J Nizet Victor V Vollmer Waldemar W Winkler Malcolm E ME Veening Jan-Willem JW

Nature microbiology 20251219 1

S protein is conserved among streptococci and contributes to group A Streptococcus virulence, but the mechanisms involved are unclear. Here we used genetic, biochemical, single-molecule, in vitro and in vivo analyses to show that S protein is crucial for resistance against host-derived antimicrobials by coordinating cell wall modification and repair. We observed that S protein was localized to the streptococcal septum dependent on its transmembrane domain, while S protein function was dependent ...[more]

PMID: 41420059

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Project description:Streptococcus pneumoniae is a human commensal bacterium that causes serious diseases. Peptidoglycan (PG) is the critical component of bacteria that maintains cell shape, size, chaining, and turgor resistance. Because of its surface exposure and eubacterial-specific mechanism of biosynthesis, PG biosynthesis remains an outstanding target for discovery of new antibiotics to resistant “superbugs,” like S. pneumoniae. Pneumococcal PG biosynthesis is carried out by a balance of septal and peripheral (side-wall-like) PG synthesis mediated by bPBP2x and bPBP2b, respectively, that emanates from midcell regions. We selected for additional suppressor mutations, besides mltG, that eliminate the requirement for essential bPBP2b in peripheral PG synthesis. We found that mutations that inactivate a putative RNA binding protein, designated KhpA, suppressed the requirement for some, but not all of the essential proteins required for peripheral PG synthesis. KhpA was used as bait in co-IP experiments to demonstrate interactions with a second RNA binding protein, designated KhpB, in cells. Mutations in khpA or khpB phenocopy each other and result in slower growth rates, smaller cell size with normal aspect ratios, and induction of cell wall stress responses. RIP-Seq analyses confirmed KhpAB as RNA binding protein in cells. Another suppressor of Δpbp2b implicated induction of a cell division operon as a way to bypass the requirement for bPBP2b. We show that increased expression of this cell division operon occurs in ΔkhpAB mutants and that this induction is necessary and sufficient to account for suppression of Δpbp2b. Comparisons of relative transcript amounts and protein levels indicate that induction of this cell division operon in ΔkhpAB mutants occurs primarily at the post-transcriptional level. Together, our results show that KhpAB, which are virulence factors in S. pneumoniae and are conserved in other Gram-positive pathogens, acts as a new class of RNA binding protein, with properties analogous to Hfq in Gram-negative bacteria.

			Action	DRS
	220121_Gallay_14139.raw	Raw
	220121_Gallay_14145.raw	Raw
	F008880.dat	Other
	F008880.mgf	Mgf
	F008880.mzid.gz	Mzid