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

Lookup NU author(s): Jessica Burnier, Dr Daniela Vollmer, Dr Jacob BiboyORCiD, Professor Waldemar Vollmer, Dr Jan-Willem Veening

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Abstract

© The Author(s), under exclusive licence to Springer Nature Limited 2025. 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 on its peptidoglycan (PG)-binding LysM domain. Direct interactions between the pneumococcal S protein and the PG synthase PBP1a as well as the PG deacetylase PgdA were detected. Loss of S protein reduced the proportion of circumferentially moving PBP1a molecules, altered streptococcal morphology and increased susceptibility to cell-wall-targeting antibiotics, suggesting that S protein activates PBP1a. Streptococcus pneumoniae ess mutants lacking the gene encoding S protein were more susceptible to human antimicrobial peptide LL-37 and lysozyme, while their virulence was decreased compared with wild-type bacteria in zebrafish and mice. These data suggest that S protein activates the PG repair and modification complex, providing defence against host-derived and environmental antimicrobials.

Publication metadata

Author(s): Burnier J, Gallay C, Bruce KE, Bjanes E, Martin L, Jim KK, Tsui H-CT, Cremers AJH, Mignolet J, Vollmer D, Biboy J, Nizet V, Vollmer W, Winkler ME, Veening J-W

Publication type: Article

Publication status: Published

Journal: Nature Microbiology

Year: 2026

Volume: 11

Pages: 282-300

Print publication date: 01/01/2026

Online publication date: 19/12/2025

Acceptance date: 09/10/2025

ISSN (electronic): 2058-5276

Publisher: Springer Nature

URL: https://doi.org/10.1038/s41564-025-02184-4

DOI: 10.1038/s41564-025-02184-4

PubMed id: 41420059

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