Ribonucleotide reductase, a novel drug target for gonorrhea
- PTC Therapeutics, Inc., United States
- Bristol Myers Squibb, United States
- Schrödinger, Inc., United States
- PMV Pharmaceuticals, United States
- Massachusetts Institute of Technology, United States
- Howard Hughes Medical Institute, Massachusetts Institute of Technology, United States
- PTC Therapeutics Inc, United States
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
Catherine L Drennan
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.
Reviewing Editor
- Amie K Boal, Pennsylvania State University, United States
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
Version history
- Preprint posted: November 20, 2020 (view preprint)
- Received: February 11, 2021
- Accepted: February 8, 2022
- Accepted Manuscript published: February 9, 2022 (version 1)
- Version of Record published: February 23, 2022 (version 2)
- Version of Record updated: March 10, 2022 (version 3)
- Version of Record updated: March 17, 2022 (version 4)
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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Ribonucleotide reductase, a novel drug target for gonorrhea
eLife 11:e67447.
https://doi.org/10.7554/eLife.67447
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