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Ribonucleotide reductase, a novel drug target for gonorrhea.
- Source :
-
eLife . 2/23/2022, p1-26. 26p. - Publication Year :
- 2022
-
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. [ABSTRACT FROM AUTHOR]
Details
- Language :
- English
- ISSN :
- 2050084X
- Database :
- Academic Search Index
- Journal :
- eLife
- Publication Type :
- Academic Journal
- Accession number :
- 155447753
- Full Text :
- https://doi.org/10.7554/eLife.67447