Ribonucleotide reductase, a novel drug target for gonorrhea
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....
| Main Authors: | , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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eLife Sciences Publications Ltd
2022-02-01
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| Series: | eLife |
| Subjects: | |
| Online Access: | https://elifesciences.org/articles/67447 |
| _version_ | 1811236089188319232 |
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| author | 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 |
| author_facet | 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 |
| author_sort | Jana Narasimhan |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-04-12T12:02:58Z |
| format | Article |
| id | doaj.art-e2f24e41f41645fe97c9ca6615d7120b |
| institution | Directory Open Access Journal |
| issn | 2050-084X |
| language | English |
| last_indexed | 2024-04-12T12:02:58Z |
| publishDate | 2022-02-01 |
| publisher | eLife Sciences Publications Ltd |
| record_format | Article |
| series | eLife |
| spelling | doaj.art-e2f24e41f41645fe97c9ca6615d7120b2022-12-22T03:33:48ZengeLife Sciences Publications LtdeLife2050-084X2022-02-011110.7554/eLife.67447Ribonucleotide reductase, a novel drug target for gonorrheaJana Narasimhan0https://orcid.org/0000-0001-5621-8592Suzanne Letinski1Stephen P Jung2https://orcid.org/0000-0002-9276-175XAleksey Gerasyuto3Jiashi Wang4Michael Arnold5Guangming Chen6Jean Hedrick7Melissa Dumble8Kanchana Ravichandran9Talya Levitz10Chang Cui11Catherine L Drennan12https://orcid.org/0000-0001-5486-2755JoAnne Stubbe13https://orcid.org/0000-0001-8076-4489Gary Karp14Arthur Branstrom15https://orcid.org/0000-0002-5917-6372PTC Therapeutics, Inc, South Plainfield, United StatesPTC Therapeutics, Inc, South Plainfield, United StatesPTC Therapeutics, Inc, South Plainfield, United StatesPTC Therapeutics, Inc, South Plainfield, United StatesPTC Therapeutics, Inc, South Plainfield, United StatesPTC Therapeutics, Inc, South Plainfield, United StatesPTC Therapeutics, Inc, South Plainfield, United StatesPTC Therapeutics, Inc, South Plainfield, United StatesPTC Therapeutics, Inc, South Plainfield, United StatesDepartment of Chemistry, Massachusetts Institute of Technology, Cambridge, United StatesDepartment of Biology, Massachusetts Institute of Technology, Cambridge, United StatesDepartment of Chemistry and Chemical Biology, Harvard University, Cambridge, United StatesDepartment of Chemistry, Massachusetts Institute of Technology, Cambridge, United States; Department of Biology, Massachusetts Institute of Technology, Cambridge, United States; Howard Hughes Medical Institute, Massachusetts Institute of Technology, Cambridge, United StatesDepartment of Chemistry, Massachusetts Institute of Technology, Cambridge, United States; Department of Biology, Massachusetts Institute of Technology, Cambridge, United StatesPTC Therapeutics, Inc, South Plainfield, United StatesPTC Therapeutics, Inc, South Plainfield, United StatesAntibiotic-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.https://elifesciences.org/articles/67447neisseria gonorrhoeaegonorrhearibonucleotide reductasemultidrug resistance2-pyridone |
| spellingShingle | 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 Ribonucleotide reductase, a novel drug target for gonorrhea eLife neisseria gonorrhoeae gonorrhea ribonucleotide reductase multidrug resistance 2-pyridone |
| title | Ribonucleotide reductase, a novel drug target for gonorrhea |
| title_full | Ribonucleotide reductase, a novel drug target for gonorrhea |
| title_fullStr | Ribonucleotide reductase, a novel drug target for gonorrhea |
| title_full_unstemmed | Ribonucleotide reductase, a novel drug target for gonorrhea |
| title_short | Ribonucleotide reductase, a novel drug target for gonorrhea |
| title_sort | ribonucleotide reductase a novel drug target for gonorrhea |
| topic | neisseria gonorrhoeae gonorrhea ribonucleotide reductase multidrug resistance 2-pyridone |
| url | https://elifesciences.org/articles/67447 |
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