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Substituted Furanocoumarins as Novel Class of Antibacterial Translation Inhibitors

[ Vol. 22 , Issue. 6 ]

Author(s):

Yan A. Ivanenkov, Renat S. Yamidanov, Ilya A. Osterman, Petr V. Sergiev, Andrey A. Ayginin*, Vladimir A. Aladinskiy, Anastasia V. Aladinskaya, Victor A. Terentiev, Mark S. Veselov, Dmitry A. Skvortsov, Katerina S. Komarova, Alexey V. Chemeris, Liana F. Zainullina, Marina A. Maximova, Zulfiya R. Zileeva, Yulia V. Vakhitova, Alexey Kh. Baymiev, Andrey Kh. Baymiev, Alina A. Sofronova, Alexey E. Machulkin, Rostislav A. Petrov, Dmitry S. Bezrukov, Maria M. Puchinina, Dmitrii A. Lukianov and Olga A. Dontsova   Pages 400 - 410 ( 11 )

Abstract:


Introduction: 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.

Methods: 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).

Results: 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.

Conclusion: 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.

Keywords:

Antibiotics, antibacterial compounds, HTS, translation inhibition, furanocoumarins, ribosome.

Affiliation:

Institute of Biochemistry and Genetics Russian Academy of Science (IBG RAS) Ufa Scientific Centre, Oktyabrya Prospekt 71, 450054, Ufa, Institute of Biochemistry and Genetics Russian Academy of Science (IBG RAS) Ufa Scientific Centre, Oktyabrya Prospekt 71, 450054, Ufa, Skolkovo Institute of Science and Technology, Skolkovo, Skolkovo Institute of Science and Technology, Skolkovo, Institute of Biochemistry and Genetics Russian Academy of Science (IBG RAS) Ufa Scientific Centre, Oktyabrya Prospekt 71, 450054, Ufa, Moscow Institute of Physics and Technology (State University), 9 Institutskiy lane, Dolgoprudny City, Moscow Region 141700, Moscow Institute of Physics and Technology (State University), 9 Institutskiy lane, Dolgoprudny City, Moscow Region 141700, Institute of Biochemistry and Genetics Russian Academy of Science (IBG RAS) Ufa Scientific Centre, Oktyabrya Prospekt 71, 450054, Ufa, Institute of Biochemistry and Genetics Russian Academy of Science (IBG RAS) Ufa Scientific Centre, Oktyabrya Prospekt 71, 450054, Ufa, Lomonosov Moscow State University, Department of Chemistry and A.N. Belozersky Institute of Physico-Chemical Biology, Moscow, Lomonosov Moscow State University, Department of Chemistry and A.N. Belozersky Institute of Physico-Chemical Biology, Moscow, Institute of Biochemistry and Genetics Russian Academy of Science (IBG RAS) Ufa Scientific Centre, Oktyabrya Prospekt 71, 450054, Ufa, Institute of Biochemistry and Genetics Russian Academy of Science (IBG RAS) Ufa Scientific Centre, Oktyabrya Prospekt 71, 450054, Ufa, Institute of Biochemistry and Genetics Russian Academy of Science (IBG RAS) Ufa Scientific Centre, Oktyabrya Prospekt 71, 450054, Ufa, Institute of Biochemistry and Genetics Russian Academy of Science (IBG RAS) Ufa Scientific Centre, Oktyabrya Prospekt 71, 450054, Ufa, Institute of Biochemistry and Genetics Russian Academy of Science (IBG RAS) Ufa Scientific Centre, Oktyabrya Prospekt 71, 450054, Ufa, Institute of Biochemistry and Genetics Russian Academy of Science (IBG RAS) Ufa Scientific Centre, Oktyabrya Prospekt 71, 450054, Ufa, Institute of Biochemistry and Genetics Russian Academy of Science (IBG RAS) Ufa Scientific Centre, Oktyabrya Prospekt 71, 450054, Ufa, Lomonosov Moscow State University, Faculty of Bioengineering and Bioinformatics, Moscow, Lomonosov Moscow State University, Chemistry Dept, Leninskie Gory, Building 1/3, GSP-1, Moscow 119991, Lomonosov Moscow State University, Chemistry Dept, Leninskie Gory, Building 1/3, GSP-1, Moscow 119991, Lomonosov Moscow State University, Chemistry Dept, Leninskie Gory, Building 1/3, GSP-1, Moscow 119991, Moscow Institute of Physics and Technology (State University), 9 Institutskiy lane, Dolgoprudny City, Moscow Region 141700, Skolkovo Institute of Science and Technology, Skolkovo, Skolkovo Institute of Science and Technology, Skolkovo



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