Structure-guided microbial targeting of antistaphylococcal prodrugs

  1. Justin J Miller
  2. Ishaan T Shah
  3. Jayda Hatten
  4. Yasaman Barekatain
  5. Elizabeth A Mueller
  6. Ahmed M Moustafa
  7. Rachel L Edwards
  8. Cynthia S Dowd
  9. Paul Planet
  10. Florian L Muller
  11. Joseph Jez
  12. Audrey R Odom John  Is a corresponding author
  1. Washington University School of Medicine, United States
  2. The University of Texas MD Anderson Cancer Center, United States
  3. Washington University in St Louis, United States
  4. Children's Hospital of Philadelphia, United States
  5. The George Washington University, United States

Abstract

Carboxy ester prodrugs are widely employed to increase oral absorption and potency of phosphonate antibiotics. Prodrugging can mask problematic chemical features that prevent cellular uptake and may enable tissue specific compound delivery. However, many carboxy ester promoieties are rapidly hydrolyzed by serum esterases, limiting their therapeutic potential. While carboxy ester-based prodrug targeting is feasible, it has seen limited use in microbes as microbial esterase specific promoieties have not been described. Here we identify the bacterial esterases, GloB and FrmB, that activate carboxy ester prodrugs in Staphylococcus aureus. Additionally, we determine the substrate specificities for FrmB and GloB and demonstrate the structural basis of these preferences. Finally, we establish the carboxy ester substrate specificities of human and mouse sera, ultimately identifying several promoieties likely to be serum esterase-resistant and microbially labile. These studies will enable structure-guided design of anti-staphylococcal promoieties and expand the range of molecules to target staphylococcal pathogens.

Data availability

Sequencing data and structure data is provided in the manuscript and deposited on the NCBI BioProject database (PRJNA648156) or in the protein data bank (FrmB accession code 7L0A, GloB accession code 7L0B).

The following data sets were generated

Article and author information

Author details

  1. Justin J Miller

    Pediatrics, Washington University School of Medicine, Saint Louis, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-9400-8916
  2. Ishaan T Shah

    Pediatrics, Washington University School of Medicine, Saint Louis, United States
    Competing interests
    The authors declare that no competing interests exist.
  3. Jayda Hatten

    Pediatrics, Washington University School of Medicine, Saint Louis, United States
    Competing interests
    The authors declare that no competing interests exist.
  4. Yasaman Barekatain

    Cancer Systems Imaging, The University of Texas MD Anderson Cancer Center, Houston, United States
    Competing interests
    The authors declare that no competing interests exist.
  5. Elizabeth A Mueller

    Biology, Washington University in St Louis, St Louis, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-5482-6551
  6. Ahmed M Moustafa

    Pediatrics Infectious Diseases, Children's Hospital of Philadelphia, Philadelphia, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-9949-6936
  7. Rachel L Edwards

    Pediatrics, Washington University School of Medicine, Saint Louis, United States
    Competing interests
    The authors declare that no competing interests exist.
  8. Cynthia S Dowd

    Chemistry, The George Washington University, Washington DC, United States
    Competing interests
    The authors declare that no competing interests exist.
  9. Paul Planet

    Pediatrics Infectious Diseases, Children's Hospital of Philadelphia, Philadelphia, United States
    Competing interests
    The authors declare that no competing interests exist.
  10. Florian L Muller

    Cancer Systems Imaging, The University of Texas MD Anderson Cancer Center, Houston, United States
    Competing interests
    The authors declare that no competing interests exist.
  11. Joseph Jez

    Biology, Washington University in St Louis, St Louis, United States
    Competing interests
    The authors declare that no competing interests exist.
  12. Audrey R Odom John

    Pediatrics, Children's Hospital of Philadelphia, Philadelphia, United States
    For correspondence
    johna3@email.chop.edu
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-8395-8537

Funding

National Institutes of Health (R01 AI103280; R21 AI123808; R21 AI130584)

  • Audrey R Odom John

National Center for Research Resources (UL1 RR024992)

  • Joseph Jez

Burroughs Wellcome Fund (PATH)

  • Audrey R Odom John

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Reviewing Editor

  1. Bavesh D Kana, University of the Witwatersrand, South Africa

Publication history

  1. Preprint posted: December 15, 2020 (view preprint)
  2. Received: January 18, 2021
  3. Accepted: July 16, 2021
  4. Accepted Manuscript published: July 19, 2021 (version 1)
  5. Version of Record published: July 28, 2021 (version 2)
  6. Version of Record updated: November 25, 2021 (version 3)

Copyright

© 2021, Miller et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

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  1. Justin J Miller
  2. Ishaan T Shah
  3. Jayda Hatten
  4. Yasaman Barekatain
  5. Elizabeth A Mueller
  6. Ahmed M Moustafa
  7. Rachel L Edwards
  8. Cynthia S Dowd
  9. Paul Planet
  10. Florian L Muller
  11. Joseph Jez
  12. Audrey R Odom John
(2021)
Structure-guided microbial targeting of antistaphylococcal prodrugs
eLife 10:e66657.
https://doi.org/10.7554/eLife.66657

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