Dataset Information

Molecular recognition of sialoglycans by streptococcal Siglec-like adhesins: toward the shape of specific inhibitors.

ABSTRACT: Streptococcus gordonii and Streptococcus sanguinis, commensal bacteria present in the oral cavity of healthy individuals, upon entry into the bloodstream can become pathogenic, causing infective endocarditis (IE). Sialic acid-binding serine-rich repeat adhesins on the microbial surface represent an important factor of successful infection to cause IE. They contain Siglec-like binding regions (SLBRs) that variously recognize different repertoires of O-glycans, with some strains displaying high selectivity and others broader specificity. We here dissect at an atomic level the mechanism of interaction of SLBR-B and SLBR-H from S. gordonii with a multivarious approach that combines NMR spectroscopy and computational and biophysical studies. The binding pockets of both SLBRs are broad enough to accommodate extensive interactions with sialoglycans although with key differences related to strain specificity. Furthermore, and significantly, the pattern of interactions established by the SLBRs are mechanistically very different from those reported for mammalian Siglecs despite them having a similar fold. Thus, our detailed description of the binding modes of streptococcal Siglec-like adhesins sparks the development of tailored synthetic inhibitors and therapeutics specific for Streptococcal adhesins to counteract IE, without impairing the interplay between Siglecs and glycans.

SUBMITTER: Di Carluccio C

PROVIDER: S-EPMC8637897 | biostudies-literature | 2021 Dec

REPOSITORIES: biostudies-literature

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Publications

Molecular recognition of sialoglycans by streptococcal Siglec-like adhesins: toward the shape of specific inhibitors.

Di Carluccio Cristina C Forgione Rosa Ester RE Bosso Andrea A Yokoyama Shinji S Manabe Yoshiyuki Y Pizzo Elio E Molinaro Antonio A Fukase Koichi K Fragai Marco M Bensing Barbara A BA Marchetti Roberta R Silipo Alba A

RSC chemical biology 20211018 6

Streptococcus gordonii and Streptococcus sanguinis, commensal bacteria present in the oral cavity of healthy individuals, upon entry into the bloodstream can become pathogenic, causing infective endocarditis (IE). Sialic acid-binding serine-rich repeat adhesins on the microbial surface represent an important factor of successful infection to cause IE. They contain Siglec-like binding regions (SLBRs) that variously recognize different repertoires of O-glycans, with some strai ...[more]

PMID: 34977577

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Project description:Damaged cardiac valves attract blood-borne bacteria, and infective endocarditis is often caused by viridans group streptococci. While such bacteria use multiple adhesins to maintain their normal oral commensal state, recognition of platelet sialoglycans provides an intermediary for binding to damaged valvular endocardium. We use a customized sialoglycan microarray to explore the varied binding properties of phylogenetically related serine-rich repeat adhesins, the GspB, Hsa, and SrpA homologs from Streptococcus gordonii and Streptococcus sanguinis species, which belong to a highly conserved family of glycoproteins that contribute to virulence for a broad range of Gram-positive pathogens. Binding profiles of recombinant soluble homologs containing novel sialic acid-recognizing Siglec-like domains correlate well with binding of corresponding whole bacteria to arrays. These bacteria show multiple modes of glycan, protein, or divalent cation-dependent binding to synthetic glycoconjugates and isolated glycoproteins in vitro. However, endogenous asialoglycan-recognizing clearance receptors are known to ensure that only fully sialylated glycans dominate in the endovascular system, wherein we find these particular streptococci become primarily dependent on their Siglec-like adhesins for glycan-mediated recognition events. Remarkably, despite an excess of alternate sialoglycan ligands in cellular and soluble blood components, these adhesins selectively target intact bacteria to sialylated ligands on platelets, within human whole blood. These preferred interactions are inhibited by corresponding recombinant soluble adhesins, which also preferentially recognize platelets. Our data indicate that circulating platelets may act as inadvertent Trojan horse carriers of oral streptococci to the site of damaged endocardium, and provide an explanation why it is that among innumerable microbes that gain occasional access to the bloodstream, certain viridans group streptococci have a selective advantage in colonizing damaged cardiac valves and cause infective endocarditis.

Dataset Information

Molecular recognition of sialoglycans by streptococcal Siglec-like adhesins: toward the shape of specific inhibitors.

Publications

Molecular recognition of sialoglycans by streptococcal Siglec-like adhesins: toward the shape of specific inhibitors.

Similar Datasets

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