Identification of novel antistaphylococcal hit compounds

Recently, the article dedicated to the development of novel antistaphylococcal agents targeting seryl-tRNA synthetase has been published.

Abstract:

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 antistaphylococcal 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 conpound 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. At the same time, this compound does not reveal antibacterial activity toward Escherichia coli ATCC 47076. Therefore, this compound can be proposed as effective antiseptic toward multidrug-resistant biofilm-forming S. aureus isolates. 

• Identification of novel antistaphylococcal hit compounds. Volynets GP, Iungin OS, Gudzera OI, Vyshniakova HV, Rybak MYu, Moshynets OV, Balanda AO, Borovykov OV, Prykhod'ko AO, Lukashov SS, Maiula TH, Pletnova LV, Yarmoluk SM, Tukalo MA. The Journal of Antibiotics. 2024,  77:665-678.