Tetrahydrocarbazoles as Novel Class of DNA Biosynthesis Inhibitors in Bacteria

Author(s): Yan A. Ivanenkov*, Ilya A. Osterman, Ekaterina S. Komarova, Alexey A. Bogdanov, Petr V. Sergiev, Olga A. Dontsova, Alina A. Sofronova, Victor A. Terentiev, Gleb I. Filkov, Renat S. Yamidanov, Alexander G. Majouga, Dmitry S. Bezrukov, Ekaterina V. Deyneka, Dmitry A. Skvortsov

Journal Name: Anti-Infective Agents
Anti-Infective Agents in Medicinal Chemistry

Volume 18 , Issue 2 , 2020

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Abstract:

Background: High-throughput screening (HTS) of large-compound libraries is a convenient and cost-effective tool for novel drug discovery. However, in many cases, HTS platforms are not well adapted to perform cell-based screening assay with simultaneous identification of the mechanism of action for active compounds.

Methods: Previously, we have described a unique double-reporter system that can be used to reveal compounds having antibacterial activity. This construction is based on two genes of Katushka2S and RFP that encode proteins with different imaging signature. The upregulated expression of the first gene attributes directly to translation inhibition in prokaryotes while the high expression of the second one is unambiguously associated with DNA biosynthesis restriction (SOS-response).

Results: In the current work, we have applied this system for the identification of novel smallmolecule compounds with antibacterial activity in HTS scale. Compounds were selected from the ChemDiv in-house collection (of total 47K molecules) following the maximum diversity in structure. Based on the obtained results, we have revealed a small series of tetrahydrocarbazole derivatives with antibacterial activity. The hit compound inhibited bacterial growth with a MIC value of 21 μg/ml and blocked DNA biosynthesis. No activity towards translation has been observed. In spite of a relatively moderate potency, as compared to the control sample (erythromycin, MIC=3 μg/ml), this molecule provides good selectivity index (SI>333, HEK239).

Conclusion: Tetrahydrocarbazole derivatives can be properly regarded as an attractive starting point for further development and optimization.

Keywords: Screening, antibacterial activity, DNA biosynthesis inhibitors, tetrahydrocarbazoles, reporter strain, bacteria.

[1]
Entzeroth, M.; Flotow, H.; Condron, P. Overview of High-Throughput Screening. Curr. Protoc. Pharmacol.,, 2009. Chapter 9,Unit 9.4.
[http://dx.doi.org/10.1002/0471141755.ph0904s44]
[2]
Kohanski, M.A.; Dwyer, D.J.; Collins, J.J. How antibiotics kill bacteria: from targets to networks. Nat. Rev. Microbiol., 2010, 8(6), 423-435.
[http://dx.doi.org/10.1038/nrmicro2333] [PMID: 20440275]
[3]
Saxena, S.; Renuka, J.; Jeankumar, V.U.; Yogeeswari, P.; Sriram, D. Mycobacterial DNA gyrB inhibitors: Ligand based pharmacophore modelling and in vitro enzyme inhibition studies. Curr. Top. Med. Chem., 2014, 14(17), 1990-2005.
[http://dx.doi.org/10.2174/1568026613666140929123833] [PMID: 25262795]
[4]
Osterman, I.A.; Prokhorova, I.V.; Sysoev, V.O.; Boykova, Y.V.; Efremenkova, O.V.; Svetlov, M.S.; Kolb, V.A.; Bogdanov, A.A.; Sergiev, P.V.; Dontsova, O.A. Attenuation-based dual-fluorescent-protein reporter for screening translation inhibitors. Antimicrob. Agents Chemother., 2012, 56(4), 1774-1783.
[http://dx.doi.org/10.1128/AAC.05395-11] [PMID: 22252829]
[5]
Ysern, P.; Clerch, B.; Castańo, M.; Gibert, I.; Barbé, J.; Llagostera, M. Induction of SOS genes in Escherichia coli and mutagenesis in Salmonella typhimurium by fluoroquinolones. Mutagenesis, 1990, 5(1), 63-66.
[http://dx.doi.org/10.1093/mutage/5.1.63] [PMID: 2158613]
[6]
Komarova (Andreyanova),E.S.; Osterman, I.A.; Pletnev, P.I.; Ivanenkov, Y.A.; Majouga, A.G.; Bogdanov, A.A.; Sergiev, P.V. 2-guanidino-quinazolines as a novel class of translation inhibitors. Biochimie, 2017, 133, 45-55.
[http://dx.doi.org/10.1016/j.biochi.2016.11.008]
[7]
Osterman, I.A.; Komarova, E.S.; Shiryaev, D.I.; Korniltsev, I.A.; Khven, I.M.; Lukyanov, D.A.; Tashlitsky, V.N.; Serebryakova, M.V.; Efremenkova, O.V.; Ivanenkov, Y.A.; Bogdanov, A.A.; Sergiev, P.V.; Dontsova, O.A. Sorting Out Antibiotics’ Mechanisms of Action: a Double Fluorescent Protein Reporter for High-Throughput Screening of Ribosome and DNA Biosynthesis Inhibitors. Antimicrob. Agents Chemother., 2016, 60(12), 7481-7489.
[http://dx.doi.org/10.1128/AAC.02117-16] [PMID: 27736765]
[8]
Shcherbo, D.; Murphy, C.S.; Ermakova, G.V.; Solovieva, E.A.; Chepurnykh, T.V.; Shcheglov, A.S.; Verkhusha, V.V.; Pletnev, V.Z.; Hazelwood, K.L.; Roche, P.M.; Lukyanov, S.; Zaraisky, A.G.; Davidson, M.W.; Chudakov, D.M. Far-red fluorescent tags for protein imaging in living tissues. Biochem. J., 2009, 418(3), 567-574.
[http://dx.doi.org/10.1042/BJ20081949] [PMID: 19143658]
[9]
Merzlyak, E.M.; Goedhart, J.; Shcherbo, D.; Bulina, M.E.; Shcheglov, A.S.; Fradkov, A.F.; Gaintzeva, A.; Lukyanov, K.A.; Lukyanov, S.; Gadella, T.W.J.; Chudakov, D.M. Bright monomeric red fluorescent protein with an extended fluorescence lifetime. Nat. Methods, 2007, 4(7), 555-557.
[http://dx.doi.org/10.1038/nmeth1062] [PMID: 17572680]
[10]
Baba, T.; Mori, H. The Construction of Systematic In-Frame, Single-Gene Knockout Mutant Collection in Escherichia Coli K-12. Microbial Gene Essentiality: Protocols and Bioinformatics; Methods in Molecular Biology; Humana Press, 2008, pp. 171-181.
[http://dx.doi.org/10.1007/978-1-59745-321-9_11]
[11]
Wiegand, I.; Hilpert, K.; Hancock, R.E. Agar and broth dilution methods to determine the minimal inhibitory concentration (MIC) of antimicrobial substances. Nat. Protoc., 2008, 3(2), 163-175.
[http://dx.doi.org/10.1038/nprot.2007.521] [PMID: 18274517]
[12]
Głuszyńska, A. Biological potential of carbazole derivatives. Eur. J. Med. Chem., 2015, 94, 405-426.
[http://dx.doi.org/10.1016/j.ejmech.2015.02.059] [PMID: 25794500]
[13]
Tsutsumi, L.S.; Gündisch, D.; Sun, D. carbazole scaffold in medicinal chemistry and natural products: a review from 2010-2015. Curr. Top. Med. Chem., 2016, 16(11), 1290-1313.
[http://dx.doi.org/10.2174/1568026615666150915112647] [PMID: 26369811]
[14]
Bashir, M.; Bano, A.; Ijaz, A.S.; Chaudhary, B.A. recent developments and biological activities of n-substituted carbazole derivatives: a review. Molecules, 2015, 20(8), 13496-13517.
[http://dx.doi.org/10.3390/molecules200813496] [PMID: 26213906]
[15]
Caruso, A.; Iacopetta, D.; Puoci, F.; Cappello, A.R.; Saturnino, C.; Sinicropi, M.S. Carbazole derivatives: a promising scenario for breast cancer treatment. Mini Rev. Med. Chem., 2016, 16(8), 630-643.
[http://dx.doi.org/10.2174/1389557515666150709111342] [PMID: 26156543]
[16]
Sun, L.; Wu, Y.; Liu, Y.; Chen, X.; Hu, L. Novel carbazole sulfonamide derivatives of antitumor agent: Synthesis, antiproliferative activity and aqueous solubility. Bioorg. Med. Chem. Lett., 2017, 27(2), 261-265.
[http://dx.doi.org/10.1016/j.bmcl.2016.11.068] [PMID: 27919655]
[17]
Yin, Z.; Whittell, L.R.; Wang, Y.; Jergic, S.; Liu, M.; Harry, E.J.; Dixon, N.E.; Beck, J.L.; Kelso, M.J.; Oakley, A.J. Discovery of lead compounds targeting the bacterial sliding clamp using a fragment-based approach. J. Med. Chem., 2014, 57(6), 2799-2806.
[http://dx.doi.org/10.1021/jm500122r] [PMID: 24592885]
[18]
Nakahara, K.; Trakoontivakorn, G.; Alzoreky, N.S.; Ono, H.; Onishi-Kameyama, M.; Yoshida, M. Antimutagenicity of some edible Thai plants, and a bioactive carbazole alkaloid, mahanine, isolated from Micromelum minutum. J. Agric. Food Chem., 2002, 50(17), 4796-4802.
[http://dx.doi.org/10.1021/jf025564w] [PMID: 12166962]
[19]
Wang, P.Y.; Fang, H.S.; Shao, W.B.; Zhou, J.; Chen, Z.; Song, B.A.; Yang, S. Synthesis and biological evaluation of pyridinium-functionalized carbazole derivatives as promising antibacterial agents. Bioorg. Med. Chem. Lett., 2017, 27(18), 4294-4297.
[http://dx.doi.org/10.1016/j.bmcl.2017.08.040] [PMID: 28843708]
[20]
Tachibana, Y.; Kikuzaki, H.; Lajis, N.H.; Nakatani, N. Antioxidative activity of carbazoles from Murraya koenigii leaves. J. Agric. Food Chem., 2001, 49(11), 5589-5594.
[http://dx.doi.org/10.1021/jf010621r] [PMID: 11714364]
[21]
Saturnino, C.; Iacopetta, D.; Sinicropi, M.S.; Rosano, C.; Caruso, A.; Caporale, A.; Marra, N.; Marengo, B.; Pronzato, M.A.; Parisi, O.I.; Longo, P.; Ricciarelli, R. N-alkyl carbazole derivatives as new tools for Alzheimer’s disease: preliminary studies. Molecules, 2014, 19(7), 9307-9317.
[http://dx.doi.org/10.3390/molecules19079307] [PMID: 24991761]


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Article Details

VOLUME: 18
ISSUE: 2
Year: 2020
Page: [121 - 127]
Pages: 7
DOI: 10.2174/2211352517666181218155259

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