Laboratory for Medicinal Chemistry (FFW) , Ghent University , Ottergemsesteenweg 460 , B-9000 Gent , Belgium.
VIB Center for Inflammation Research , Zwijnaarde, Ghent 9052 , Belgium.
J Med Chem. 2018 Apr 12;61(7):2753-2775. doi: 10.1021/acs.jmedchem.7b01570. Epub 2018 Mar 15.
In recent years, thymidylate kinase (TMPK), an enzyme indispensable for bacterial DNA biosynthesis, has been pursued for the development of new antibacterial agents including against Mycobacterium tuberculosis, the causative agent for the widespread infectious disease tuberculosis (TB). In response to a growing need for more effective anti-TB drugs, we have built upon our previous efforts toward the exploration of novel and potent Mycobacterium tuberculosis TMPK ( MtTMPK) inhibitors, and reported here the design of a novel series of non-nucleoside inhibitors of MtTMPK. The inhibitors display hitherto unexplored interactions in the active site of MtTMPK, offering new insights into structure-activity relationships. To investigate the discrepancy between enzyme inhibitory activity and the whole-cell activity, experiments with efflux pump inhibitors and efflux pump knockout mutants were performed. The minimum inhibitory concentrations of particular inhibitors increased significantly when determined for the efflux pump mmr knockout mutant, which partly explains the observed dissonance.
近年来，胸苷酸激酶（TMPK）作为细菌 DNA 生物合成所必需的酶，已被广泛用于开发新的抗菌药物，包括治疗结核分枝杆菌（导致广泛传染性疾病肺结核（TB）的病原体）。为了满足对更有效抗结核药物的日益增长的需求，我们在前人探索新型强效结核分枝杆菌 TMPK（MtTMPK）抑制剂的基础上，设计了一系列新型非核苷 MtTMPK 抑制剂。这些抑制剂在 MtTMPK 的活性部位显示出迄今未知的相互作用，为构效关系提供了新的见解。为了研究酶抑制活性与全细胞活性之间的差异，进行了外排泵抑制剂和外排泵敲除突变体的实验。当针对外排泵 mmr 敲除突变体确定特定抑制剂的最小抑菌浓度时，其显著增加，这部分解释了观察到的不和谐。
