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TitleMultivalent nanobodies for potent and broad neutralization of Staphylococcus aureus toxins.
Journal, issue, pagesNat Commun, Vol. 17, Issue 1, Year 2026
Publish dateMay 20, 2026
AuthorsYong Joon Jeffrey Kim / Nicholas R Walton / Wei Huang / Madison Lee / Yufei Xiang / Zhe Sang / Chaya Sussman / Sarah K L Moore / Derek J Taylor / Kong Chen / Jaime L Hook / John K McCormick / Yi Shi /
PubMed AbstractStaphylococcus aureus is a leading cause of lethal bacteremia and pneumonia, which are driven by potent virulence factors such as T-cell superantigens and alpha hemolysin. S. aureus has among the ...Staphylococcus aureus is a leading cause of lethal bacteremia and pneumonia, which are driven by potent virulence factors such as T-cell superantigens and alpha hemolysin. S. aureus has among the highest rates of antibiotic resistance, yet no vaccines or alternative therapies are available. Here, we developed a repertoire of potent, high-affinity nanobodies (Nbs) targeting key toxins in S. aureus infection, including Hla and superantigens SEB, SEC, and TSST-1. Comprehensive cryo-EM and AlphaFold3 analyses of these Nbs, which were elicited with clinical cocktail vaccines, revealed diverse neutralizing epitopes and mechanisms that provide insights for immunotherapy and vaccine strategies. Guided by these findings, we engineered stable, multivalent, and multifunctional Nb constructs. These constructs included an aerosolizable trimeric Nb with enhanced neutralization activity against Hla and SEC, and a decameric Nb-IgG-Fc fusion construct with pM or better potencies against a wide range of major toxins in S. aureus sepsis (SEB, SEC, TSST-1, and Hla). These multifunctional Nbs demonstrated protective activity in murine models of pneumonia and sepsis, underscoring their potential as versatile immunotherapies that address the complex virulence of S. aureus. Our work lays a foundation for precision immunotherapies beyond current treatment options to combat complex bacterial infections with multiple virulence mechanisms.
External linksNat Commun / PubMed:42161902 / PubMed Central
MethodsEM (single particle)
Resolution3.1 Å
Structure data

72377

9xzx

EMDB-72377, PDB-9xzx:
Staphylococcal Enterotoxin C in complex with NB C107 and NB C112
Method: EM (single particle) / Resolution: 3.1 Å

Chemicals

ChemComp-ZN:
Unknown entry

Source
  • Homo sapiens (human)
  • staphylococcus aureus (bacteria)
  • lama glama (llama)
KeywordsIMMUNE SYSTEM / Nanobody / VHH

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