Ribonucleotide reductase, a novel drug target for gonorrhea.

Abstract

Antibiotic-resistant <i>Neisseria gonorrhoeae (Ng</i>) 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 <i>Ng</i> 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 <i>Ng</i> 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 <i>Ng</i> RNR and reveal that allosteric effector dATP potentiates the inhibitory effect. Oral administration of PTC-672 reduces <i>Ng</i> infection in a mouse model and may have therapeutic potential for treatment of <i>Ng</i> that is resistant to current drugs.