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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 α 4 β 4  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.

Ribonucleotide reductase, a novel drug target for gonorrhea