Identification of novel antistaphylococcal hit compounds

• Published in: Journal of antibiotics 2024-10, Vol.77 (10), p.665-678
• Main Authors: Volynets, Galyna P., Iungin, Olga S., Gudzera, Olga I., Vyshniakova, Hanna V., Rybak, Mariia Yu, Moshynets, Olena V., Balanda, Anatoliy O., Borovykov, Oleksiy V., Prykhod’ko, Andrii O., Lukashov, Sergiy S., Maiula, Taras H., Pletnova, Larysa V., Yarmoluk, Sergiy M., Tukalo, Michael A.
• Format: Article
• Language: English
• Subjects: 631/154/1435/2163; 631/326/46; 82; 82/80; Activity recognition; Antibacterial activity; Antibiotics; Antiinfectives and antibacterials; Bacteriology; Biofilms; Biomedical and Life Sciences; Bioorganic Chemistry; Clinical isolates; Escherichia coli; Life Sciences; Medicinal Chemistry; Microbiology; Minimum inhibitory concentration; Molecular docking; Multidrug resistance; Nosocomial infection; Organic Chemistry; Serine-tRNA ligase; Staphylococcus aureus; Therapeutic targets; Transfer RNA; tRNA
• ISSN: 0021-8820; 1881-1469; 1881-1469
• DOI: 10.1038/s41429-024-00752-0

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-(1 H -imidazol-1-methyl-2-yl)-5-nitro-1 H -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-4 H -[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.