Ribonucleotide reductase, a novel drug target for gonorrhea
Name
elife-67447-v4.pdf
Description
Published version
Size
5.15 MB
Format
Adobe PDF
Checksum (MD5)
ef509cef1590988bc82e824306a1b9c1
Author(s)
Narasimhan, Jana
Letinski, Suzanne
Jung, Stephen P
Gerasyuto, Aleksey
Wang, Jiashi
Arnold, Michael
Chen, Guangming
Hedrick, Jean
Dumble, Melissa
Ravichandran, Kanchana
Date Issued
2022
Journal
eLife
Publisher
eLife Sciences Publications, Ltd
Citation
Narasimhan, Jana, Letinski, Suzanne, Jung, Stephen P, Gerasyuto, Aleksey, Wang, Jiashi et al. 2022. "Ribonucleotide reductase, a novel drug target for gonorrhea." eLife, 11.
Version
Final published version
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 α4β4 state in the presence of the β 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.
MIT Department
Massachusetts Institute of Technology. Department of Biology
Massachusetts Institute of Technology. Department of Chemistry
Terms of Use
Creative Commons Attribution 4.0 International license
Persistent DSpace Link
DOI of Published Version
https://doi.org/10.7554/ELIFE.67447
