Lipid analogs reveal features critical for hemolysis and diminish granadaene mediated Group B Streptococcus infection

Blair Armistead, Pilar Herrero-Foncubierta, Michelle Coleman, Phoenicia Quach, Christopher Whidbey, Jose Justicia, Ruben Tapia, Raquel Casares, Alba Millán, Ali Haidour, Javier Rodriguez Granger, Jay Vornhagen, Verónica Santana-Ufret, Sean Merillat, Kristina Adams Waldorf, Juan Manuel Cuerva () and Lakshmi Rajagopal ()
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Blair Armistead: University of Washington
Pilar Herrero-Foncubierta: University of Granada
Michelle Coleman: Seattle Children’s Research Institute
Phoenicia Quach: Seattle Children’s Research Institute
Christopher Whidbey: University of Washington
Jose Justicia: University of Granada
Ruben Tapia: University of Granada
Raquel Casares: University of Granada
Alba Millán: University of Granada
Ali Haidour: University of Granada
Javier Rodriguez Granger: Virgen de las Nieves Hospital
Jay Vornhagen: University of Washington
Verónica Santana-Ufret: Seattle Children’s Research Institute
Sean Merillat: Seattle Children’s Research Institute
Kristina Adams Waldorf: University of Washington
Juan Manuel Cuerva: University of Granada
Lakshmi Rajagopal: University of Washington

Nature Communications, 2020, vol. 11, issue 1, 1-12

Abstract: Abstract Although certain microbial lipids are toxins, the structural features important for cytotoxicity remain unknown. Increased functional understanding is essential for developing therapeutics against toxic microbial lipids. Group B Streptococci (GBS) are bacteria associated with preterm births, stillbirths, and severe infections in neonates and adults. GBS produce a pigmented, cytotoxic lipid, known as granadaene. Despite its importance to all manifestations of GBS disease, studies towards understanding granadaene’s toxic activity are hindered by its instability and insolubility in purified form. Here, we report the synthesis and screening of lipid derivatives inspired by granadaene, which reveal features central to toxin function, namely the polyene chain length. Furthermore, we show that vaccination with a non-toxic synthetic analog confers the production of antibodies that inhibit granadaene-mediated hemolysis ex vivo and diminish GBS infection in vivo. This work provides unique structural and functional insight into granadaene and a strategy to mitigate GBS infection, which will be relevant to other toxic lipids encoded by human pathogens.

Date: 2020
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DOI: 10.1038/s41467-020-15282-0

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