University of Ljubljana, Faculty of Pharmacy, Aškerčeva cesta 7, 1000, Ljubljana, Slovenia.
Synthetic and Systems Biology Unit, Institute of Biochemistry, Biological Research Centre of the Hungarian Academy of Sciences, Szeged, H-6726, Hungary.
Eur J Med Chem. 2019 Apr 1;167:269-290. doi: 10.1016/j.ejmech.2019.02.004. Epub 2019 Feb 10.
ATP competitive inhibitors of DNA gyrase and topoisomerase IV have great therapeutic potential, but none of the described synthetic compounds has so far reached the market. To optimise the activities and physicochemical properties of our previously reported N-phenylpyrrolamide inhibitors, we have synthesized an improved, chemically variegated selection of compounds and evaluated them against DNA gyrase and topoisomerase IV enzymes, and against selected Gram-positive and Gram-negative bacteria. The most potent compound displayed IC values of 6.9 nM against Escherichia coli DNA gyrase and 960 nM against Staphylococcus aureus topoisomerase IV. Several compounds displayed minimum inhibitory concentrations (MICs) against Gram-positive strains in the 1-50 μM range, one of which inhibited the growth of Enterococcus faecalis, Enterococcus faecium, S. aureus and Streptococcus pyogenes with MIC values of 1.56 μM, 1.56 μM, 0.78 μM and 0.72 μM, respectively. This compound has been investigated further on methicillin-resistant S. aureus (MRSA) and on ciprofloxacin non-susceptible and extremely drug resistant strain of S. aureus (MRSA VISA). It exhibited the MIC value of 2.5 μM on both strains, and MIC value of 32 μM against MRSA in the presence of inactivated human blood serum. Further studies are needed to confirm its mode of action.
DNA 拓扑异构酶 II 和 IV 的 ATP 竞争性抑制剂具有很大的治疗潜力，但迄今为止，没有一种已描述的合成化合物进入市场。为了优化我们之前报道的 N-苯基吡咯酰胺抑制剂的活性和理化性质，我们合成了一组改进的、化学多样化的化合物，并对其进行了评估，以对抗 DNA 拓扑异构酶 II 和 IV 酶，以及针对选定的革兰氏阳性和革兰氏阴性细菌。最有效的化合物对大肠杆菌 DNA 拓扑异构酶 II 的 IC 值为 6.9 nM，对金黄色葡萄球菌拓扑异构酶 IV 的 IC 值为 960 nM。几种化合物对革兰氏阳性菌的最小抑菌浓度（MIC）在 1-50 μM 范围内，其中一种化合物对粪肠球菌、屎肠球菌、金黄色葡萄球菌和化脓性链球菌的生长具有抑制作用，MIC 值分别为 1.56 μM、1.56 μM、0.78 μM 和 0.72 μM。该化合物已进一步针对耐甲氧西林金黄色葡萄球菌（MRSA）和对环丙沙星不敏感且耐多药的金黄色葡萄球菌（MRSA VISA）进行了研究。在人血灭活血清存在的情况下，它对两种菌株的 MIC 值均为 2.5 μM，对 MRSA 的 MIC 值为 32 μM。需要进一步的研究来确认其作用模式。
