1. Microbiology and Infectious Disease

Ribonucleotide reductase, a novel drug target for gonorrhea

  1. Jana Narasimhan  Is a corresponding author
  2. Suzanne Letinski
  3. Stephen P Jung
  4. Aleksey Gerasyuto
  5. Jiashi Wang
  6. Michael Arnold
  7. Guangming Chen
  8. Jean Hedrick
  9. Melissa Dumble
  10. Kanchana Ravichandran
  11. Talya Levitz
  12. Cui Chang
  13. Catherine L Drennan
  14. JoAnne Stubbe  Is a corresponding author
  15. Gary Karp
  16. Arthur Branstrom  Is a corresponding author
  1. PTC Therapeutics, Inc., United States
  2. Bristol Myers Squibb, United States
  3. Schrödinger, Inc., United States
  4. PMV Pharmaceuticals, United States
  5. Massachusetts Institute of Technology, United States
  6. Howard Hughes Medical Institute, Massachusetts Institute of Technology, United States
  7. PTC Therapeutics Inc, United States
https://doi.org/10.7554/eLife.67447
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  1. Jana Narasimhan
  2. Suzanne Letinski
  3. Stephen P Jung
  4. Aleksey Gerasyuto
  5. Jiashi Wang
  6. Michael Arnold
  7. Guangming Chen
  8. Jean Hedrick
  9. Melissa Dumble
  10. Kanchana Ravichandran
  11. Talya Levitz
  12. Cui Chang
  13. Catherine L Drennan
  14. JoAnne Stubbe
  15. Gary Karp
  16. Arthur Branstrom
(2022)
Ribonucleotide reductase, a novel drug target for gonorrhea
eLife 11:e67447.
https://doi.org/10.7554/eLife.67447
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Abstract

Antibiotic resistant Neisseria gonorrhoeae (Ng) are an emerging public health threat due to increasing numbers of multidrug resistant (MDR) organisms. We identified two novel orally active inhibitors, PTC-847 and PTC-672, that exhibit a narrow spectrum of activity against Ng including MDR isolates. By selecting organisms resistant to the novel inhibitors and sequencing their genomes, we identified a new therapeutic target, the class Ia ribonucleotide reductase (RNR). Resistance mutations in Ng map to the N-terminal cone domain of the α subunit, which we show here is involved in forming an inhibited a4b4 state in the presence of the b subunit and allosteric effector dATP. Enzyme assays confirm that PTC-847 and PTC-672 inhibit Ng RNR and reveal that allosteric effector dATP potentiates the inhibitory effect. Oral administration of PTC-672 reduces Ng infection in a mouse model and may have therapeutic potential for treatment of Ng that is resistant to current drugs.

Data availability

All data generated or analyzed during this study are included in the manuscript and supplemental section.

Article and author information

Author details

  1. Jana Narasimhan

    Pharmacology and Biomarkers, PTC Therapeutics, Inc., South Plainfield, United States
    For correspondence
    jnarasimhan@ptcbio.com
    Competing interests
    Jana Narasimhan, was employed by PTC Therapeutics when the work was performed and received salary and compensation during their tenure..
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-5621-8592

  2. Suzanne Letinski

    Analytical Development and Attribute Sciences, Bristol Myers Squibb, New Brunswick, United States
    Competing interests
    Suzanne Letinski, was employed by PTC Therapeutics when the work was performed and received salary and compensation during their tenure..

  3. Stephen P Jung

    Pharmacology and Biomarkers, PTC Therapeutics, Inc., South Plainfield, United States
    Competing interests
    Stephen P Jung, was employed by PTC Therapeutics when the work was performed and received salary and compensation during their tenure..
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-9276-175X

  4. Aleksey Gerasyuto

    Medicinal Chemistry, Schrödinger, Inc., New York, United States
    Competing interests
    Aleksey Gerasyuto, was employed by PTC Therapeutics when the work was performed and received salary and compensation during their tenure..

  5. Jiashi Wang

    Medicinal Chemistry, Schrödinger, Inc., New York, United States
    Competing interests
    Jiashi Wang, was employed by PTC Therapeutics when the work was performed and received salary and compensation during their tenure..

  6. Michael Arnold

    Chemistry, PTC Therapeutics, Inc., South Plainfield, United States
    Competing interests
    Michael Arnold, Arnold,were employed by PTC Therapeutics when the work wasperformed and received salary and compensation during their tenure.

  7. Guangming Chen

    Chemistry, PTC Therapeutics, Inc., South Plainfield, United States
    Competing interests
    Guangming Chen, was employed by PTC Therapeutics when the work was performed and received salary and compensation during their tenure..

  8. Jean Hedrick

    Pharmacology and Biomarkers, PTC Therapeutics, Inc., South Plainfield, United States
    Competing interests
    Jean Hedrick, was employed by PTC Therapeutics when the work was performed and received salary and compensation during their tenure..

  9. Melissa Dumble

    Preclinical Development and Translational Science, PMV Pharmaceuticals, Cranbury, United States
    Competing interests
    Melissa Dumble, was employed by PTC Therapeutics when the work was performed and received salary and compensation during their tenure..

  10. Kanchana Ravichandran

    Department of Chemistry, Massachusetts Institute of Technology, Cambridge, United States
    Competing interests
    No competing interests declared.

  11. Talya Levitz

    Department of Biology, Massachusetts Institute of Technology, Cambridge, United States
    Competing interests
    No competing interests declared.

  12. Cui Chang

    Department of Biology, Massachusetts Institute of Technology, Cambridge, United States
    Competing interests
    No competing interests declared.

  13. Catherine L Drennan

    Department of Biology, Howard Hughes Medical Institute, Massachusetts Institute of Technology, Cambridge, United States
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-5486-2755

  14. JoAnne Stubbe

    Department of Chemistry, Massachusetts Institute of Technology, Cambridge, United States
    For correspondence
    stubbe@mit.edu
    Competing interests
    No competing interests declared.

  15. Gary Karp

    Chemistry, PTC Therapeutics, Inc., South Plainfield, United States
    Competing interests
    Gary Karp, was employed by PTC Therapeutics when the work was performed and received salary and compensation during their tenure..

  16. Arthur Branstrom

    Biology, PTC Therapeutics Inc, South Plainfield, United States
    For correspondence
    abranstrom@ptcbio.com
    Competing interests
    Arthur Branstrom, was employed by PTC Therapeutics when the work was performed and received salary and compensation during their tenure.

Funding

Wellcome Trust (097753)

  • Arthur Branstrom

National Institutes of Health (GM126982)

  • Catherine L Drennan

National Institutes of Health (GM007287)

  • Talya Levitz

National Science Foundation (2017246757)

  • Talya Levitz

National Institutes of Health (GM29595)

  • JoAnne Stubbe

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

Ethics

Animal experimentation: Animal studies were done according to procedures reviewed and approved by the Rutgers Institutional Animal Care and Use Committee (IACUC). The IACUC protocol ID used was I12-075-12

Copyright

© 2022, Narasimhan 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. Jana Narasimhan
  2. Suzanne Letinski
  3. Stephen P Jung
  4. Aleksey Gerasyuto
  5. Jiashi Wang
  6. Michael Arnold
  7. Guangming Chen
  8. Jean Hedrick
  9. Melissa Dumble
  10. Kanchana Ravichandran
  11. Talya Levitz
  12. Cui Chang
  13. Catherine L Drennan
  14. JoAnne Stubbe
  15. Gary Karp
  16. Arthur Branstrom
(2022)
Ribonucleotide reductase, a novel drug target for gonorrhea
eLife 11:e67447.
https://doi.org/10.7554/eLife.67447

Share this article

https://doi.org/10.7554/eLife.67447

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