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Development of a New Inhibitor of Bacterial Cystathionine γ-Lyase Based on 6-Bromoindole and Aminothiophene
- Authors: Novikov R.A.1,2, Platonov D.N.2, Bely A.Y.2, Potapov K.V.1,2, Novikov M.A.1,2, Tomilov Y.V.2, Kechko O.I.1, Seregina T.A.1, Solyev P.N.1, Mitkevich V.A.1
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Affiliations:
- Engelhardt Institute of Molecular Biology of the Russian Academy of Sciences
- Zelinsky Institute of Organic Chemistry of the Russian Academy of Sciences
- Issue: Vol 58, No 6 (2024)
- Pages: 975-982
- Section: ПОЛУЧЕНИЕ И СТРУКТУРНО-ФУНКЦИОНАЛЬНЫЙ АНАЛИЗ ПРОТИВОМИКРОБНЫХ СРЕДСТВ
- URL: https://innoscience.ru/0026-8984/article/view/677886
- DOI: https://doi.org/10.31857/S0026898424060083
- EDN: https://elibrary.ru/IAYTTU
- ID: 677886
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Abstract
Cystathionine γ-lyase (CSE) is a key enzyme for the H2S generation in such pathogenic bacteria as Staphylococcus aureus, Pseudomonas aeruginosa, etc. Suppression of CSE activity significantly increases the sensitivity of bacteria to the action of antibiotics. Here, we present a method for the synthesis of a novel indole-based CSE inhibitor, 3-amino-5-[(6-bromo-1H-indol-1-yl)methyl]thiophene, named MNS1. The synthesis of this compound is based on the modification of substituted thiophene as the main structural fragment, which is involved the alkylation of 6-bromoindole at the final stages. The dissociation constant of the MNS1 complex with bacterial CSE (from S. aureus, SaCSE) was 0.5 μM, which was an order of magnitude lower than that for human CSE (hCSE). The MNS1 compound was shown to effectively enhance the antibacterial effect of gentamicin against Bacillus subtilis, allowing it to be used as an antibiotic potentiator, to inhibit the growth of CSE-expressing bacterial cells.
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About the authors
R. A. Novikov
Engelhardt Institute of Molecular Biology of the Russian Academy of Sciences; Zelinsky Institute of Organic Chemistry of the Russian Academy of Sciences
Email: solyev@gmail.com
Russian Federation, Moscow, 119991; Moscow, 119991
D. N. Platonov
Zelinsky Institute of Organic Chemistry of the Russian Academy of Sciences
Email: solyev@gmail.com
Russian Federation, Moscow, 119991
A. Yu. Bely
Zelinsky Institute of Organic Chemistry of the Russian Academy of Sciences
Email: solyev@gmail.com
Russian Federation, Moscow, 119991
K. V. Potapov
Engelhardt Institute of Molecular Biology of the Russian Academy of Sciences; Zelinsky Institute of Organic Chemistry of the Russian Academy of Sciences
Email: solyev@gmail.com
Russian Federation, Moscow, 119991; Moscow, 119991
M. A. Novikov
Engelhardt Institute of Molecular Biology of the Russian Academy of Sciences; Zelinsky Institute of Organic Chemistry of the Russian Academy of Sciences
Email: solyev@gmail.com
Russian Federation, Moscow, 119991; Moscow, 119991
Yu. V. Tomilov
Zelinsky Institute of Organic Chemistry of the Russian Academy of Sciences
Email: solyev@gmail.com
Russian Federation, Moscow, 119991
O. I. Kechko
Engelhardt Institute of Molecular Biology of the Russian Academy of Sciences
Email: solyev@gmail.com
Russian Federation, Moscow, 119991
T. A. Seregina
Engelhardt Institute of Molecular Biology of the Russian Academy of Sciences
Email: solyev@gmail.com
Russian Federation, Moscow, 119991
P. N. Solyev
Engelhardt Institute of Molecular Biology of the Russian Academy of Sciences
Author for correspondence.
Email: solyev@gmail.com
Russian Federation, Moscow, 119991
V. A. Mitkevich
Engelhardt Institute of Molecular Biology of the Russian Academy of Sciences
Email: solyev@gmail.com
Russian Federation, Moscow, 119991
References
- Miller W.R., Arias C.A. (2024) ESKAPE pathogens: antimicrobial resistance, epidemiology, clinical impact and therapeutics. Nat. Rev. Microbiol. 22(10), 598–616. https://doi.org/10.1038/s41579-024-01054-w
- Shatalin K., Nuthanakanti A., Kaushik A., Shishov D., Peselis A., Shamovsky I., Pani B., Lechpammer M., Vasilyev N., Shatalina A., Rebatchouk D., Mironov A., Fedichev P., Serganov A., Nudler E. (2021) Inhibitors of bacterial H2S biogenesis targeting antibiotic resistance and tolerance. Science. 372, 1169–1175.
- Solyev P.N., Isakova E.B., Olsufyeva E.N. (2023) Antibacterial conjugates of kanamycin A with vancomycin and eremomycin: biological activity and a new MS-fragmentation pattern of Cbz-protected amines. Antibiotics. 12, 894.
- Mariasina S.S., Chang C.F., Petrova O.A., Efimov S.V., Klochkov V.V., Kechko O.I., Mitkevich V.A., Sergiev P.V., Dontsova O.A., Polshakov V.I. (2020) Williams–Beuren syndrome-related methyltransferase WBSCR27: cofactor binding and cleavage. FEBS J. 287, 5375–5393.
- Clinical and Laboratory Standards Institute. (2015) Method for Dilution Antimicrobial Susceptibility Test for Bacteria that Grow Aerobically; Approved Standard, 10th edition. CLSI document M07–A10. National Committee for Clinical and Laboratory Standards, Wayne PA.
- Forbes B.A. (1998) Bailey and Scott's Diagnostic Microbiology, 10th edition. St. Louis, MO: Mosby, 1069 p.
- Potapov K.V., Novikov R.A., Novikov M.A., Solyev P.N., Tomilov Y.V., Kochetkov S.N., Makarov A.A., Mitkevich V.A. (2023) Synthesis of the indole-based inhibitors of bacterial cystathionine γ-lyase NL1–NL3. Molecules. 28, 3568.
- Novikov M.A., Potapov K.V., Novikov R.A., Solyev P.N., Tomilov Y.V., Kochetkov S.N., Makarov A.A., Mitkevich V.A. (2024) A convenient synthesis of a chlorobenzothiophenyl-indole-based inhibitor of bacterial cystathionine γ-lyase. Mendeleev Commun. 34, 255–258.
- Huddleston P. R., Barker J. M. (1979) A convenient synthesis of 2-substituted 3-hydroxy- and 3-amino-thiophens from derivatives of 2-chloroacrylic acid. Synthetic Commun. 9, 731–734.
- Pedretti M., Fernández-Rodríguez C., Conter C., Oyenarte I., Favretto F., di Matteo A., Dominici P., Petrosino M., Martinez-Chantar M.L., Majtan T., Astegno A., Martínez-Cruz L.A. (2024) Catalytic specificity and crystal structure of cystathionine γ-lyase from Pseudomonas aeruginosa. Sci. Rep. 14, 9364.
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