TY - JOUR TI - 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 A2 - Boal, Amie K A2 - Kana, Bavesh D VL - 11 PY - 2022 DA - 2022/02/09 SP - e67447 C1 - eLife 2022;11:e67447 DO - 10.7554/eLife.67447 UR - https://doi.org/10.7554/eLife.67447 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. KW - neisseria gonorrhoeae KW - gonorrhea KW - ribonucleotide reductase KW - multidrug resistance KW - 2-pyridone JF - eLife SN - 2050-084X PB - eLife Sciences Publications, Ltd ER -