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Large-scale High-throughput Screening Revealed 5'-(carbonylamino)-2,3'- bithiophene-4'-carboxylate as Novel Template for Antibacterial Agents

[ Vol. 17 , 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, Bogdan A. Zagribelnyy*, Alexey Kh. Baimiev, Kseniya Yu. Shvetc, Andrey Kh. Baimiev, Alina A. Sofronova, Alexey E. Machulkin, Rostislav A. Petrov, Liana F. Zainullina, Marina A. Maximova, Zulfiya R. Zileeva, Yulia V. Vakhitova, Dmitry S. Bezrukov, Maria M. Puchinina and Olga A. Dontsova   Pages 716 - 724 ( 9 )

Abstract:


Background: The key issue in the development of novel antimicrobials is a rapid expansion of new bacterial strains resistant to current antibiotics. Indeed, World Health Organization has reported that bacteria commonly causing infections in hospitals and in the community, e.g. E. Coli, K. pneumoniae and S. aureus, have high resistance vs the last generations of cephalosporins, carbapenems and fluoroquinolones. During the past decades, only few successful efforts to develop and launch new antibacterial medications have been performed. This study aims to identify new class of antibacterial agents using novel high-throughput screening technique.

Methods: We have designed library containing 125K compounds not similar in structure (Tanimoto coeff.< 0.7) to that published previously as antibiotics. The HTS platform based on double reporter system pDualrep2 was used to distinguish between molecules able to block translational machinery or induce SOS-response in a model E. coli system. MICs for most active chemicals in LB and M9 medium were determined using broth microdilution assay.

Results: In an attempt to discover novel classes of antibacterials, we performed HTS of a large-scale small molecule library using our unique screening platform. This approach permitted us to quickly and robustly evaluate a lot of compounds as well as to determine the mechanism of action in the case of compounds being either translational machinery inhibitors or DNA-damaging agents/replication blockers. HTS has resulted in several new structural classes of molecules exhibiting an attractive antibacterial activity. Herein, we report as promising antibacterials. Two most active compounds from this series showed MIC value of 1.2 (5) and 1.8 μg/mL (6) and good selectivity index. Compound 6 caused RFP induction and low SOS response. In vitro luciferase assay has revealed that it is able to slightly inhibit protein biosynthesis. Compound 5 was tested on several archival strains and exhibited slight activity against gram-negative bacteria and outstanding activity against S. aureus. The key structural requirements for antibacterial potency were also explored. We found, that the unsubstituted carboxylic group is crucial for antibacterial activity as well as the presence of bulky hydrophobic substituents at phenyl fragment.

Conclusion: The obtained results provide a solid background for further characterization of the 5'- (carbonylamino)-2,3'-bithiophene-4'-carboxylate derivatives discussed herein as new class of antibacterials and their optimization campaign.

Keywords:

Antibiotics, antibacterial, HTS, 2, 3'-Bithiophene, MIC, high-throughput screening.

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, Lomonosov Moscow State University, Chemistry Dept, Leninskie gory, Building 1/3, GSP-1, Moscow, 119991, Skolkovo Institute of Science and Technology, Skolkovo, 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, 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, Lomonosov Moscow State University, Chemistry Dept, Leninskie gory, Building 1/3, GSP-1, Moscow, 119991, 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, 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, Moscow Institute of Physics and Technology (State University), 9 Institutskiy lane, Dolgoprudny City, Moscow Region, 141700, Lomonosov Moscow State University, Chemistry Dept, Leninskie gory, Building 1/3, GSP-1, Moscow, 119991

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