Ivanenkov Yan A, Yamidanov Renat S, Osterman Ilya A, Sergiev Petr V, Ayginin Andrey A, Aladinskiy Vladimir A, Aladinskaya Anastasia V, Terentiev Victor A, Veselov Mark S, Skvortsov Dmitry A, Komarova Katerina S, Chemeris Alexey V, Zainullina Liana F, Maximova Marina A, Zileeva Zulfiya R, Vakhitova Yulia V, Baymiev Alexey Kh, Baymiev Andrey Kh, Sofronova Alina A, Machulkin Alexey E, Petrov Rostislav A, Bezrukov Dmitry S, Puchinina Maria M, Lukianov Dmitrii A, Dontsova Olga A
Institute of Biochemistry and Genetics Russian Academy of Science (IBG RAS) Ufa Scientific Centre, Oktyabrya Prospekt 71, 450054, Ufa, Russian Federation.
Moscow Institute of Physics and Technology (State University), 9 Institutskiy lane, Dolgoprudny City, Moscow Region 141700, Russian Federation.
Comb Chem High Throughput Screen. 2019;22(6):400-410. doi: 10.2174/1386207322666190723110539.
A variety of organic compounds has been reported to have antibacterial activity. However, antimicrobial resistance is one of the main problems of current anti-infective therapy, and the development of novel antibacterials is one of the main challenges of current drug discovery.
Using our previously developed dual-reporter High-Throughput Screening (HTS) platform, we identified a series of furanocoumarins as having high antibacterial activity. The construction of the reporter system allows us to differentiate three mechanisms of action for the active compounds: inhibition of protein synthesis (induction of Katushka2S), DNA damaging (induction of RFP) or other (inhibition of bacterial growth without reporter induction).
Two primary hit-molecules of furanocoumarin series demonstrated relatively low MIC values comparable to that observed for Erythromycin (Ery) against E. coli and weakly induced both reporters. Dose-dependent translation inhibition was shown using in vitro luciferase assay, however it was not confirmed using C14-test. A series of close structure analogs of the identified hits was obtained and investigated using the same screening platform. Compound 19 was found to have slightly lower MIC value (15.18 µM) and higher induction of Katushka2S reporter in contrast to the parent structures. Moreover, translation blockage was clearly identified using both in vitro luciferase assay and C14 test. The standard cytotoxicity test revealed a relatively low cytotoxicity of the most active molecules.
High antibacterial activity in combination with low cytotoxicity was demonstrated for a series of furanocoumarins. Further optimization of the described structures may result in novel and attractive lead compounds with promising antibacterial efficiency.
据报道，多种有机化合物具有抗菌活性。然而，抗菌耐药性是当前抗感染治疗的主要问题之一，开发新型抗菌药物是当前药物研发的主要挑战之一。
利用我们之前开发的双报告基因高通量筛选（HTS）平台，我们鉴定出一系列具有高抗菌活性的呋喃香豆素。报告系统的构建使我们能够区分活性化合物的三种作用机制：抑制蛋白质合成（诱导Katushka2S）、DNA损伤（诱导RFP）或其他（抑制细菌生长而不诱导报告基因）。
呋喃香豆素系列的两个主要命中分子表现出相对较低的最低抑菌浓度（MIC）值，与红霉素（Ery）对大肠杆菌的MIC值相当，并且对两个报告基因的诱导作用较弱。使用体外荧光素酶测定法显示了剂量依赖性的翻译抑制，但使用C14试验未得到证实。获得了一系列已鉴定命中分子的紧密结构类似物，并使用相同的筛选平台进行了研究。与母体结构相比，化合物19的MIC值略低（15.18 µM），对Katushka2S报告基因的诱导作用更高。此外，使用体外荧光素酶测定法和C14试验均明确鉴定出翻译阻滞。标准细胞毒性试验显示，大多数活性分子的细胞毒性相对较低。
一系列呋喃香豆素表现出高抗菌活性和低细胞毒性。对所述结构的进一步优化可能会产生具有有前景抗菌效率的新型且有吸引力的先导化合物。
