Cotman Andrej Emanuel, Fulgheri Federica, Piga Martina, Peršolja Peter, Tiz Davide Benedetto, Skok Žiga, Durcik Martina, Sterle Maša, Dernovšek Jaka, Cruz Cristina D, Tammela Päivi, Szili Petra Éva, Daruka Lejla, Pál Csaba, Zega Anamarija, Mašič Lucija Peterlin, Ilaš Janez, Tomašič Tihomir, Kikelj Danijel, Zidar Nace
University of Ljubljana, Faculty of Pharmacy Aškerčeva cesta 7 1000 Ljubljana Slovenia
Drug Research Program, Division of Pharmaceutical Biosciences, Faculty of Pharmacy, University of Helsinki P.O. Box 56, Viikinkaari 5E Helsinki 00014 Finland.
RSC Adv. 2024 Sep 6;14(39):28423-28454. doi: 10.1039/d4ra04802d. eCollection 2024 Sep 4.
This study presents the discovery of a new series of -phenylpyrrolamide inhibitors of bacterial DNA gyrase with improved antibacterial activity. The most potent inhibitors had low nanomolar IC values against DNA gyrase (IC; 2-20 nM) and topoisomerase IV (22i, IC = 143 nM). Importantly, none of the compounds showed activity against human DNA topoisomerase IIα, indicating selectivity for bacterial targets. Among the tested compounds, 22e emerged as the most effective against Gram-positive bacteria with minimum inhibitory concentration (MIC) values of 0.25 μg mL against ATCC 29213 and MRSA, and 0.125 μg mL against ATCC 29212. For Gram-negative bacteria, compounds 23b and 23c showed the greatest efficacy with MIC values ranging from 4 to 32 μg mL against ATCC 25922, ATCC 27853, ATCC 17978 and ATCC 19606. Notably, compound 23b showed promising activity against the clinically relevant Gram-negative pathogen ATCC 10031, with an MIC of 0.0625 μg mL. Furthermore, compounds 23a and 23c exhibited significantly lower susceptibility to resistance development compared to novobiocin in ATCC 29213 and ATCC 10031. Overall, the most promising compounds of this series showed excellent on-target potency, marking a significant improvement over previous -phenylpyrrolamide inhibitors.
本研究报道了一系列新型的具有增强抗菌活性的β-苯基吡咯酰胺类细菌DNA促旋酶抑制剂的发现。最有效的抑制剂对DNA促旋酶（IC；2-20 nM）和拓扑异构酶IV（22i，IC = 143 nM）具有低纳摩尔IC值。重要的是，这些化合物均未显示出对人DNA拓扑异构酶IIα的活性，表明对细菌靶点具有选择性。在测试的化合物中，22e对革兰氏阳性菌最为有效，对ATCC 29213和耐甲氧西林金黄色葡萄球菌（MRSA）的最低抑菌浓度（MIC）值为0.25 μg/mL，对ATCC 29212的MIC值为0.125 μg/mL。对于革兰氏阴性菌，化合物23b和23c表现出最大的功效，对ATCC 25922、ATCC 27853、ATCC 17978和ATCC 19606的MIC值范围为4至32 μg/mL。值得注意的是，化合物23b对临床相关的革兰氏阴性病原体ATCC 10031表现出有前景的活性，MIC为0.0625 μg/mL。此外，与新生霉素相比，化合物23a和23c在ATCC 29213和ATCC 10031中对耐药性发展的敏感性显著更低。总体而言，该系列中最有前景的化合物显示出优异的靶向效力，标志着相对于先前的β-苯基吡咯酰胺抑制剂有显著改进。
