PTC Therapeutics, Inc, South Plainfield, United States.
Department of Chemistry, Massachusetts Institute of Technology, Cambridge, United States.
Elife. 2022 Feb 9;11:e67447. doi: 10.7554/eLife.67447.
Antibiotic-resistant ) 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 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 map to the N-terminal cone domain of the α subunit, which we show here is involved in forming an inhibited αβ state in the presence of the β subunit and allosteric effector dATP. Enzyme assays confirm that PTC-847 and PTC-672 inhibit RNR and reveal that allosteric effector dATP potentiates the inhibitory effect. Oral administration of PTC-672 reduces infection in a mouse model and may have therapeutic potential for treatment of that is resistant to current drugs.
由于越来越多的多药耐药（MDR）生物体的出现，抗生素耐药性是一个新出现的公共卫生威胁。我们鉴定了两种新型口服活性抑制剂 PTC-847 和 PTC-672，它们对包括 MDR 分离株在内的表现出狭窄的活性谱。通过选择对新型抑制剂有抗性的生物体并对其基因组进行测序，我们确定了一个新的治疗靶点，即 I 类核糖核苷酸还原酶（RNR）。 中的抗性突变位于 α 亚基的 N 端锥状结构域，我们在此表明，该结构域在存在β亚基和变构效应物 dATP 的情况下参与形成抑制的 αβ 状态。酶测定证实 PTC-847 和 PTC-672 抑制 RNR，并表明变构效应物 dATP 增强了抑制作用。PTC-672 的口服给药可降低小鼠模型中的 感染，并且可能具有治疗对当前药物耐药的 的治疗潜力。
