TY - JOUR
T1 - Antibody Recognition of Different Staphylococcus aureus Wall Teichoic Acid Glycoforms.
AU - Di Carluccio, Cristina
AU - Soriano-Maldonado, Pablo
AU - Berni, Francesca
AU - de Haas, Carla J C
AU - Temming, A Robin
AU - Hendriks, Astrid
AU - Ali, Sara
AU - Molinaro, Antonio
AU - Silipo, Alba
AU - van Sorge, Nina M
AU - van Raaij, Mark J
AU - Codee, Jeroen D C
AU - Marchetti, Roberta
N1 - Funding Information: This study was supported by the European Research Council (ERC) under the European Union’s Horizon 2020 research and innovation program–grant agreement No. 851356 to R.M. and H2020-MSCA-ITN-2020–grant agreement 956758 (GLYTUNES) to A.S. This study was supported by projects 91713303 of the Vidi research program (N.M.v.S., A.H.) and 09150181910001 of the Vici research program (N.M.v.S., A.R.T.), which is financed by the Dutch Research Council (NWO). This project was funded by the European Union’s Horizon 2020 research and innovation program under the Marie Skłodowska-Curie grant agreement No 675671. M.J.v.R. thanks the Spanish Ministry of Science and Innovation for grant number BFU2017-87022-P funded by MCIN/AEI/10.13039/501100011033 and by ERDF “A way of making Europe” and for the Severo Ochoa program to the CNB-CSIC (SEV 2017-0712). The staff of the XALOC-BL13 beamline at the ALBA synchrotron is acknowledged for providing excellent data collection facilities and help therewith. Publisher Copyright: © 2022 American Chemical Society. All rights reserved.
PY - 2022/10/26
Y1 - 2022/10/26
N2 - Wall teichoic acids (WTAs) are glycopolymers decorating the surface of Gram-positive bacteria and potential targets for antibody-mediated treatments against Staphylococcus aureus, including methicillin-resistant (MRSA) strains. Through a combination of glycan microarray, synthetic chemistry, crystallography, NMR, and computational studies, we unraveled the molecular and structural details of fully defined synthetic WTA fragments recognized by previously described monoclonal antibodies (mAbs 4461 and 4497). Our results unveiled the structural requirements for the discriminatory recognition of α- and β-GlcNAc-modified WTA glycoforms by the complementarity-determining regions (CDRs) of the heavy and light chains of the mAbs. Both mAbs interacted not only with the sugar moiety but also with the phosphate groups as well as residues in the ribitol phosphate (RboP) units of the WTA backbone, highlighting their significant role in ligand specificity. Using elongated WTA fragments, containing two sugar modifications, we also demonstrated that the internal carbohydrate moiety of α-GlcNAc-modified WTA is preferentially accommodated in the binding pocket of mAb 4461 with respect to the terminal moiety. Our results also explained the recently documented cross-reactivity of mAb 4497 for β-1,3/β-1,4-GlcNAc-modified WTA, revealing that the flexibility of the RboP backbone is crucial to allow positioning of both glycans in the antibody binding pocket.
AB - Wall teichoic acids (WTAs) are glycopolymers decorating the surface of Gram-positive bacteria and potential targets for antibody-mediated treatments against Staphylococcus aureus, including methicillin-resistant (MRSA) strains. Through a combination of glycan microarray, synthetic chemistry, crystallography, NMR, and computational studies, we unraveled the molecular and structural details of fully defined synthetic WTA fragments recognized by previously described monoclonal antibodies (mAbs 4461 and 4497). Our results unveiled the structural requirements for the discriminatory recognition of α- and β-GlcNAc-modified WTA glycoforms by the complementarity-determining regions (CDRs) of the heavy and light chains of the mAbs. Both mAbs interacted not only with the sugar moiety but also with the phosphate groups as well as residues in the ribitol phosphate (RboP) units of the WTA backbone, highlighting their significant role in ligand specificity. Using elongated WTA fragments, containing two sugar modifications, we also demonstrated that the internal carbohydrate moiety of α-GlcNAc-modified WTA is preferentially accommodated in the binding pocket of mAb 4461 with respect to the terminal moiety. Our results also explained the recently documented cross-reactivity of mAb 4497 for β-1,3/β-1,4-GlcNAc-modified WTA, revealing that the flexibility of the RboP backbone is crucial to allow positioning of both glycans in the antibody binding pocket.
UR - http://www.scopus.com/inward/record.url?scp=85136686120&partnerID=8YFLogxK
U2 - https://doi.org/10.1021/acscentsci.2c00125
DO - https://doi.org/10.1021/acscentsci.2c00125
M3 - Article
C2 - 36313161
SN - 2374-7943
VL - 8
SP - 1383
EP - 1392
JO - ACS central science
JF - ACS central science
IS - 10
ER -