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Therapeutic CMP-Nonulosonates against Multidrug-Resistant Neisseria gonorrhoeae

Sunita Gulati, Ian C. Schoenhofen, Theresa Lindhout-Djukic, Melissa J. Schur, Corinna S. Landig, Sudeshna Saha, Lingquan Deng, Lisa A. Lewis, Bo Zheng, Ajit Varki and Sanjay Ram
J Immunol May 20, 2020, ji1901398; DOI: https://doi.org/10.4049/jimmunol.1901398
Sunita Gulati
*Division of Infectious Diseases and Immunology, University of Massachusetts Medical School, Worcester, MA 01605;
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Ian C. Schoenhofen
†Human Health Therapeutics Research Centre, National Research Council of Canada, Ottawa, Ontario K1A 0R6, Canada;
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Theresa Lindhout-Djukic
†Human Health Therapeutics Research Centre, National Research Council of Canada, Ottawa, Ontario K1A 0R6, Canada;
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Melissa J. Schur
†Human Health Therapeutics Research Centre, National Research Council of Canada, Ottawa, Ontario K1A 0R6, Canada;
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Corinna S. Landig
‡Department of Medicine, Glycobiology Research and Training Center, University of California, San Diego, La Jolla, CA 92093; and
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Sudeshna Saha
‡Department of Medicine, Glycobiology Research and Training Center, University of California, San Diego, La Jolla, CA 92093; and
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Lingquan Deng
‡Department of Medicine, Glycobiology Research and Training Center, University of California, San Diego, La Jolla, CA 92093; and
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Lisa A. Lewis
*Division of Infectious Diseases and Immunology, University of Massachusetts Medical School, Worcester, MA 01605;
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Bo Zheng
*Division of Infectious Diseases and Immunology, University of Massachusetts Medical School, Worcester, MA 01605;
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Ajit Varki
‡Department of Medicine, Glycobiology Research and Training Center, University of California, San Diego, La Jolla, CA 92093; and
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Sanjay Ram
*Division of Infectious Diseases and Immunology, University of Massachusetts Medical School, Worcester, MA 01605;
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Key Points

  • Select NulOs displayed on gonococcal LOS render bacteria susceptible to complement.

  • CMP-NulOs show promise against multidrug-resistant gonorrhea in preclinical studies.

  • CMP-Leg5,7Ac2 and CMP-Kdn are the current lead candidates.

Abstract

Neisseria gonorrhoeae deploys a unique immune evasion strategy wherein the lacto-N-neotetraose termini of lipooligosaccharide (LOS) are “capped” by a surface LOS sialyltransferase (Lst), using extracellular host-derived CMP-sialic acid (CMP-Neu5Ac in humans). LOS sialylation enhances complement resistance by recruiting factor H (FH; alternative complement pathway inhibitor) and also by limiting classical pathway activation. Sialylated LOS also engages inhibitory Siglecs on host leukocytes, dampening innate immunity. Previously, we showed that analogues of CMP-sialic acids (CMP-nonulosonates [CMP-NulOs]), such as CMP-Leg5,7Ac2 and CMP-Neu5Ac9N3, are also substrates for Lst. Incorporation of Leg5,7Ac2 and Neu5Ac9N3 into LOS results in N. gonorrhoeae being fully serum sensitive. Importantly, intravaginal administration of CMP-Leg5,7Ac2 attenuated N. gonorrhoeae colonization of mouse vaginas. In this study, we characterize and develop additional candidate therapeutic CMP-NulOs. CMP-ketodeoxynonulosonate (CMP-Kdn) and CMP-Kdn7N3, but not CMP-Neu4,5Ac2, were substrates for Lst, further elucidating gonococcal Lst specificity. Lacto-N-neotetraose LOS capped with Kdn and Kdn7N3 bound FH to levels ∼60% of that seen with Neu5Ac and enabled gonococci to resist low (3.3%) but not higher (10%) concentrations of human complement. CMP-Kdn, CMP-Neu5Ac9N3, and CMP-Leg5,7Ac2 administered intravaginally (10 μg/d) to N. gonorrhoeae–colonized mice were equally efficacious. Of the three CMP-NulOs above, CMP-Leg5,7Ac2 was the most pH and temperature stable. In addition, Leg5,7Ac2-fed human cells did not display this NulO on their surface. Moreover, CMP-Leg5,7Ac2 was efficacious against several multidrug-resistant gonococci in mice with a humanized sialome (Cmah−/− mice) or humanized complement system (FH/C4b-binding protein transgenic mice). CMP-Leg5,7Ac2 and CMP-Kdn remain viable leads as topical preventive/therapeutic agents against the global threat of multidrug-resistant N. gonorrhoeae.

Footnotes

  • This work was supported by National Institutes of Health/National Institute of Allergy and Infectious Diseases Grants R33 AI119327 and R01 AI114790 and National Institute of General Medical Sciences Grant R01 GM32373.

  • Copyright © 2020 National Research Council of Canada

  • The online version of this article contains supplemental material.

  • Received November 22, 2019.
  • Accepted April 8, 2020.

This article is distributed under the terms of the CC BY 4.0 Unported license.

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The Journal of Immunology: 206 (3)
The Journal of Immunology
Vol. 206, Issue 3
1 Feb 2021
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Therapeutic CMP-Nonulosonates against Multidrug-Resistant Neisseria gonorrhoeae
Sunita Gulati, Ian C. Schoenhofen, Theresa Lindhout-Djukic, Melissa J. Schur, Corinna S. Landig, Sudeshna Saha, Lingquan Deng, Lisa A. Lewis, Bo Zheng, Ajit Varki, Sanjay Ram
The Journal of Immunology May 20, 2020, ji1901398; DOI: 10.4049/jimmunol.1901398

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Therapeutic CMP-Nonulosonates against Multidrug-Resistant Neisseria gonorrhoeae
Sunita Gulati, Ian C. Schoenhofen, Theresa Lindhout-Djukic, Melissa J. Schur, Corinna S. Landig, Sudeshna Saha, Lingquan Deng, Lisa A. Lewis, Bo Zheng, Ajit Varki, Sanjay Ram
The Journal of Immunology May 20, 2020, ji1901398; DOI: 10.4049/jimmunol.1901398
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