Ribonucleotide reductase, a novel drug target for gonorrhea

Jana Narasimhan; Suzanne Letinski; Stephen P. Jung; Aleksey Gerasyuto; Jiashi Wang; Michael Arnold; Guangming Chen; Jean Hedrick; Melissa Dumble; Kanchana Ravichandran; Talya Levitz; Chang Cui; Catherine L. Drennan; Joanne Stubbe; Gary Karp; Arthur Branstrom

doi:10.7554/ELIFE.67447

Ribonucleotide reductase, a novel drug target for gonorrhea

Jana Narasimhan, Suzanne Letinski, Stephen P. Jung, Aleksey Gerasyuto, Jiashi Wang, Michael Arnold, Guangming Chen, Jean Hedrick, Melissa Dumble, Kanchana Ravichandran, Talya Levitz, Chang Cui, Catherine L. Drennan, Joanne Stubbe, Gary Karp, Arthur Branstrom

Research output: Contribution to journal › Article › peer-review

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.

Original language	English (US)
Article number	e67447
Journal	eLife
Volume	11
DOIs	https://doi.org/10.7554/ELIFE.67447
State	Published - Feb 2022
Externally published	Yes

ASJC Scopus subject areas

General Neuroscience
General Biochemistry, Genetics and Molecular Biology
General Immunology and Microbiology

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10.7554/ELIFE.67447License: CC BY

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title = "Ribonucleotide reductase, a novel drug target for gonorrhea",

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.",

author = "Jana Narasimhan and Suzanne Letinski and Jung, {Stephen P.} and Aleksey Gerasyuto and Jiashi Wang and Michael Arnold and Guangming Chen and Jean Hedrick and Melissa Dumble and Kanchana Ravichandran and Talya Levitz and Chang Cui and Drennan, {Catherine L.} and Joanne Stubbe and Gary Karp and Arthur Branstrom",

note = "This project had been funded in part by the Wellcome Trust through a Seeding Drug Discovery award (097753) and by the National Institute of Health Grants R35 GM126982 (CLD) and NIH Pre-Doctoral Training grant T32 GM007287 (TSL) and NSF GRFP 2017246757 (TSL). CLD is a Howard Hughes Medical Institute Investigator. Chang Cui was supported by NIH grant GM47274 to Daniel G Nocera, Department of Chemistry at Harvard University and NIH grant GM29595 (JS). The authors wish to thank Richard Sheridan for assembling the data and getting the manuscript in submittable format.",

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doi = "10.7554/ELIFE.67447",

language = "English (US)",

volume = "11",

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TY - JOUR

T1 - Ribonucleotide reductase, a novel drug target for gonorrhea

AU - Narasimhan, Jana

AU - Letinski, Suzanne

AU - Jung, Stephen P.

AU - Gerasyuto, Aleksey

AU - Wang, Jiashi

AU - Arnold, Michael

AU - Chen, Guangming

AU - Hedrick, Jean

AU - Dumble, Melissa

AU - Ravichandran, Kanchana

AU - Levitz, Talya

AU - Cui, Chang

AU - Drennan, Catherine L.

AU - Stubbe, Joanne

AU - Karp, Gary

AU - Branstrom, Arthur

N1 - This project had been funded in part by the Wellcome Trust through a Seeding Drug Discovery award (097753) and by the National Institute of Health Grants R35 GM126982 (CLD) and NIH Pre-Doctoral Training grant T32 GM007287 (TSL) and NSF GRFP 2017246757 (TSL). CLD is a Howard Hughes Medical Institute Investigator. Chang Cui was supported by NIH grant GM47274 to Daniel G Nocera, Department of Chemistry at Harvard University and NIH grant GM29595 (JS). The authors wish to thank Richard Sheridan for assembling the data and getting the manuscript in submittable format.

PY - 2022/2

Y1 - 2022/2

N2 - 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.

AB - 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.

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Ribonucleotide reductase, a novel drug target for gonorrhea

Abstract

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