Department of Chemistry, Massachusetts Institute of Technology, Cambridge, United States; Department of Biology, Massachusetts Institute of Technology, Cambridge, United States; Howard Hughes Medical Institute, Massachusetts Institute of Technology, Cambridge, United States
Department of Chemistry, Massachusetts Institute of Technology, Cambridge, United States; Department of Biology, Massachusetts Institute of Technology, Cambridge, United States
Gary Karp
PTC Therapeutics, Inc, South Plainfield, United States
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.
