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Identification of N-Substituted Triazolo-azetidines as Novel Antibacterials using pDualrep2 HTS Platform

[ Vol. 22 , Issue. 5 ]

Author(s):

Yan A. Ivanenkov*, Renat S. Yamidanov, Ilya A. Osterman, Petr V. Sergiev, Vladimir A. Aladinskiy, Anastasia V. Aladinskaya, Victor A. Terentiev, Mark S. Veselov, Andrey A. Ayginin, Dmitry A. Skvortsov, Katerina S. Komarova, Alexey V. Chemeris, Alexey Kh. Baimiev, Alina A. Sofronova, Alexander S. Malyshev, Alexey E. Machulkin, Rostislav A. Petrov, Dmitry S. Bezrukov, Gleb I. Filkov, Maria M. Puchinina, Liana F. Zainullina, Marina A. Maximova, Zulfiya R. Zileeva, Yulia V. Vakhitova and Olga A. Dontsova   Pages 346 - 354 ( 9 )

Abstract:


Aim and Objective: Antibiotic resistance is a serious constraint to the development of new effective antibacterials. Therefore, the discovery of the new antibacterials remains one of the main challenges in modern medicinal chemistry. This study was undertaken to identify novel molecules with antibacterial activity.

Materials and Methods: Using our unique double-reporter system, in-house large-scale HTS campaign was conducted for the identification of antibacterial potency of small-molecule compounds. The construction allows us to visually assess the underlying mechanism of action. After the initial HTS and rescreen procedure, luciferase assay, C14-test, determination of MIC value and PrestoBlue test were carried out.

Results: HTS rounds and rescreen campaign have revealed the antibacterial activity of a series of Nsubstituted triazolo-azetidines and their isosteric derivatives that has not been reported previously. Primary hit-molecule demonstrated a MIC value of 12.5 µg/mL against E. coli Δ tolC with signs of translation blockage and no SOS-response. Translation inhibition (26%, luciferase assay) was achieved at high concentrations up to 160 µg/mL, while no activity was found using C14-test. The compound did not demonstrate cytotoxicity in the PrestoBlue assay against a panel of eukaryotic cells. Within a series of direct structural analogues bearing the same or bioisosteric scaffold, compound 2 was found to have an improved antibacterial potency (MIC=6.25 µg/mL) close to Erythromycin (MIC=2.5-5 µg/mL) against the same strain. In contrast to the parent hit, this compound was more active and selective, and provided a robust IP position.

Conclusion: N-substituted triazolo-azetidine scaffold may be used as a versatile starting point for the development of novel active and selective antibacterial compounds.

Keywords:

Antibiotics, antibacterial compounds, HTS, translation inhibition, triazolo-azetidines, MIC, cytotoxicity, 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, 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, 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, Lomonosov Moscow State University, Faculty of Bioengineering and Bioinformatics, Moscow, Lomonosov Moscow State University, Faculty of Medicine, 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, 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, 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, Chemistry Dept, Leninskie gory, Building 1/3, GSP-1, Moscow, 119991



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