| Summary: | <jats:p>Antibiotic-resistant <jats:italic>Neisseria gonorrhoeae (Ng</jats:italic>) 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 <jats:italic>Ng</jats:italic> 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 <jats:italic>Ng</jats:italic> map to the N-terminal cone domain of the α subunit, which we show here is involved in forming an inhibited α<jats:sub>4</jats:sub>β<jats:sub>4</jats:sub> state in the presence of the β subunit and allosteric effector dATP. Enzyme assays confirm that PTC-847 and PTC-672 inhibit <jats:italic>Ng</jats:italic> RNR and reveal that allosteric effector dATP potentiates the inhibitory effect. Oral administration of PTC-672 reduces <jats:italic>Ng</jats:italic> infection in a mouse model and may have therapeutic potential for treatment of <jats:italic>Ng</jats:italic> that is resistant to current drugs.</jats:p>
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