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Information × Registration Number 0221U106084, 0120U104795 , R & D reports Title Site-directed mutagenesis as a novel strategy to investigate and overcome Mycobacterium tuberculosis antibiotic resistance popup.stage_title Head Yarmoliuk Serhii M., Доктор хімічних наук Registration Date 11-10-2021 Organization Institute of Molecular Biology and Genetics of NAS of Ukraine popup.description2  For the first time we have built ANN model and Bayesian models for search of potential M. tuberculosis MetRS inhibitors. The ROC score for ANN model was 0.74, for Bayesian models – 0.78 and 0.81. Two two-class ANN models and one Bayesian model were constructed for the search of potential M. tuberculosis LeuRS inhibitors. The ROC score values for ANN models were 0.80 and 0.93, for Bayesian model – 0.75. The ANN models also were generated for search of compounds with dual-targeted inhibitory activity toward M. tuberculosis MetRS and LeuRS. The ROC score for LeuRS models was 0.86. The ROC score for MetRS models was 0.88. 200 compounds were selected for study of their inhibitory activity toward M. tuberculosis LeuRS and MetRS using aminoacylation assay. Recombinant M. tuberculosis LeuRS and MetRS were obtained in sufficient amount. According to the results of in vitro screening we have identified for the first time 12 LeuRS inhibitors among N-phenyl-2-(quinolin-2-ylsulfanyl)-acetamide derivatives and 11 MetRS inhibitors belonging to N-(1-benzyl-1H-benzoimidazol-2-ylmethyl)-benzamides and 2-(quinolin-2-ylsulfanyl)-N-thiophen-2-yl-acetamides which decrease the activity of enzymes by more than 50% at a concentration of 100 µM. Also, we have found one inhibitor – 4,5-dimethyl-2-[2-(4-methyl-quinolin-2-ylsulfanyl)-acetylamino]-thiophene-3-carboxylic acid methyl ester, with dual-targeted activity toward M. tuberculosis MetRS and LeuRS which decreases activity of both enzymes by more than 90% at the concentration 100 µМ. The inhibitor with dual-targeted activity can be promising candidate for the development of antituberculosis agent to overcome antibiotic resistance since the likelyhood of mutations occurring simultaneously in both enzymes is negligible. Product Description popup.authors popup.nrat_date 2021-10-11 Close