Identification of novel antistaphylococcal hit compounds.

Autor: Volynets GP; Department of Medicinal Chemistry, Institute of Molecular Biology and Genetics, the NAS of Ukraine, 150 Zabolotnogo St., Kyiv, 03143, Ukraine. g.p.volynets@gmail.com., Iungin OS; Department of Functional Genomics, Institute of Molecular Biology and Genetics, the NAS of Ukraine, 150 Zabolotnogo St., Kyiv, 03143, Ukraine., Gudzera OI; Department of Protein Synthesis Enzymology, Institute of Molecular Biology and Genetics, the NAS of Ukraine, 150 Zabolotnogo St., Kyiv, 03143, Ukraine., Vyshniakova HV; Laboratory of Medical Microbiology with the Museum of Human Pathogenic Microorganisms, L.V. Gromashevsky Institute of Epidemiology and Infectious Diseases NAMS of Ukraine, 5 Amosova St., Kyiv, 03038, Ukraine., Rybak MY; Department of Microbiology and Immunology, University of Texas Medical Branch, 301 University Blvd., Galveston, TX, 77555, USA., Moshynets OV; Biofilm study group, Institute of Molecular Biology and Genetics, the NAS of Ukraine, 150 Zabolotnogo St., Kyiv, 03143, Ukraine., Balanda AO; Department of Medicinal Chemistry, Institute of Molecular Biology and Genetics, the NAS of Ukraine, 150 Zabolotnogo St., Kyiv, 03143, Ukraine., Borovykov OV; Department of Medicinal Chemistry, Institute of Molecular Biology and Genetics, the NAS of Ukraine, 150 Zabolotnogo St., Kyiv, 03143, Ukraine., Prykhod'ko AO; Department of Medicinal Chemistry, Institute of Molecular Biology and Genetics, the NAS of Ukraine, 150 Zabolotnogo St., Kyiv, 03143, Ukraine.; Research and Development Department, Scientific Services Company Otava Ltd, 150 Zabolotnogo St., Kyiv, 03143, Ukraine., Lukashov SS; Department of Medicinal Chemistry, Institute of Molecular Biology and Genetics, the NAS of Ukraine, 150 Zabolotnogo St., Kyiv, 03143, Ukraine., Maiula TH; Department of Medicinal Chemistry, Institute of Molecular Biology and Genetics, the NAS of Ukraine, 150 Zabolotnogo St., Kyiv, 03143, Ukraine.; Research and Development Department, Scientific Services Company Otava Ltd, 150 Zabolotnogo St., Kyiv, 03143, Ukraine., Pletnova LV; Department of Medicinal Chemistry, Institute of Molecular Biology and Genetics, the NAS of Ukraine, 150 Zabolotnogo St., Kyiv, 03143, Ukraine., Yarmoluk SM; Department of Medicinal Chemistry, Institute of Molecular Biology and Genetics, the NAS of Ukraine, 150 Zabolotnogo St., Kyiv, 03143, Ukraine., Tukalo MA; Department of Protein Synthesis Enzymology, Institute of Molecular Biology and Genetics, the NAS of Ukraine, 150 Zabolotnogo St., Kyiv, 03143, Ukraine.
Jazyk: angličtina
Zdroj: The Journal of antibiotics [J Antibiot (Tokyo)] 2024 Oct; Vol. 77 (10), pp. 665-678. Date of Electronic Publication: 2024 Jun 25.
DOI: 10.1038/s41429-024-00752-0
Abstrakt: Staphylococcus aureus is one of the most common nosocomial biofilm-forming pathogens worldwide that has developed resistance mechanisms against majority of the antibiotics. Therefore, the search of novel antistaphylococcal agents with unexploited mechanisms of action, especially with antibiofilm activity, is of great interest. Seryl-tRNA synthetase is recognized as a promising drug target for the development of antibacterials. We have carried out molecular docking of compounds with antistaphycoccal activity, which were earlier found by us using phenotypic screening, into synthetic site of S. aureus SerRS and found seven hit compounds with low inhibitory activity. Further, we have performed search of S. aureus SerRS inhibitors among compounds which were previously tested by us for inhibitory activity toward S. aureus ThrRS, that belong to the same class of aminoacyl-tRNA synthetases. Among them six hits were identified. We have selected four compounds for antibacterial study and found that the most active compound 1-methyl-3-(1H-imidazol-1-methyl-2-yl)-5-nitro-1H-indazole has MIC values toward S. aureus multidrug-resistant clinical isolates ranging from 78.12 to 156.2 µg/ml. However, this compound precipitated during anti-biofilm study. Therefore, we used 3-[N'-(2-hydroxy-3-methoxybenzylidene)hydrazino]-6-methyl-4H-[1,2,4]triazin-5-one with better solubility (ClogS value = 2.9) among investigated compounds toward SerRS for anti-biofilm study. It was found that this compound has a significant inhibitory effect on the growth of planktonic and biofilm culture of S. aureus 25923 with MIC value of 32 µg ml -1 . At the same time, this compound does not reveal antibacterial activity toward Esherichia coli ATCC 47076. Therefore, this compound can be proposed as effective antiseptic toward multidrug-resistant biofilm-forming S. aureus isolates.
(© 2024. The Author(s), under exclusive licence to the Japan Antibiotics Research Association.)
Databáze: MEDLINE
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