Drug Discovery and Development Centre (H3D), Department of Chemistry, University of Cape Town, Rondebosch, Cape Town 7701, South Africa.
Drug Discovery and Development Centre (H3D) South African Medical Research Council Drug Discovery and Development Research Unit, Department of Chemistry and Institute of Infectious Disease and Molecular Medicine, University of Cape Town, Rondebosch, Cape Town 7701, South Africa.
J Med Chem. 2022 May 12;65(9):6903-6925. doi: 10.1021/acs.jmedchem.2c00266. Epub 2022 May 2.
New antibiotics with either a novel mode of action or novel mode of inhibition are urgently needed to overcome the threat of drug-resistant tuberculosis (TB). The present study profiles new spiropyrimidinetriones (SPTs), DNA gyrase inhibitors having activity against drug-resistant (), the causative agent of TB. While the clinical candidate zoliflodacin has progressed to phase 3 trials for the treatment of gonorrhea, compounds herein demonstrated higher inhibitory potency against DNA gyrase (e.g., compound with IC = 2.0) and lower minimum inhibitor concentrations (0.49 μM for ). Notably, and analogues showed selective activity relative to representative Gram-positive and Gram-negative bacteria. DNA gyrase inhibition was shown to involve stabilization of double-cleaved DNA, while on-target activity was supported by hypersensitivity against a gyrA hypomorph. Finally, a docking model for SPTs with DNA gyrase was developed, and a structural hypothesis was built for structure-activity relationship expansion.
新的抗生素，具有新颖的作用模式或新颖的抑制模式，是克服耐药结核病（TB）威胁所急需的。本研究描述了新的螺吡喃嘧啶酮（SPTs），一种针对耐药性的 DNA 回旋酶抑制剂（），它是结核病的病原体。虽然临床候选药物唑利福定已进入治疗淋病的 3 期试验，但本文所述的化合物对 DNA 回旋酶具有更高的抑制效力（例如，化合物 ，IC = 2.0）和更低的最小抑制剂浓度（对 的 0.49 μM）。值得注意的是，和类似物显示出相对于代表性革兰氏阳性和革兰氏阴性细菌的选择性活性。DNA 回旋酶抑制作用涉及双链断裂 DNA 的稳定化，而靶标活性则由对 gyrA 低聚物的敏感性得到支持。最后，开发了 SPTs 与 DNA 回旋酶的对接模型，并建立了结构假设，用于扩展结构-活性关系。
