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Information × Registration Number 0223U001034, (0118U003102) , R & D reports Title Rational design of active compounds against pathogenic strains of microorganisms resistant to antibiotics popup.stage_title Раціональний дизайн активних сполук проти патогенних штамів мікроорганізмів, резистентних до лікарських засобів Head Yarmoliuk Serhii M., Доктор хімічних наук Registration Date 24-01-2023 Organization Institute of Molecular Biology and Genetics of NAS of Ukraine popup.description1 popup.description2 Using subtractive proteomics approach we have identified two new molecular targets of S. aureus - diadenylate cyclase and D-alanyl-lipoteichoic acid biosynthesis protein DltB; 9 potential molecular targets of P. aeruginosa: MreD, fumarate hydratase, protein component of ribonuclease P, dihydroneopterin aldolase, pantothenate kinase type III, enoyl-acyl-carrier protein reductase FabV and three sigma-factors of RNA polymerase; six potential novel membrane drug targets within the Acinetobacter baumannii proteome such as rod shape-determining protein RodA, DedA family protein, undecaprenyl-diphosphate phosphatase, putative lipid II flippase FtsW, prolipoprotein diacylglyceryl transferase, apolipoprotein N-acyltransferase; 6 molecular targets of E. coli: PTS system, Fru family, IIB component, the small chain of hydrogenase-2, the small chain of hydrogenase-1, Ni/Fe-hydrogenase, export ABC transporter permease LptF, export ABC transporter permease LptG. Tertiary structures of the proteins were built and ligand-binding sites were predicted. Using the methods of phenotypic screening and molecular docking we have found two S. aureus sortase A inhibitors – N,N-diethyl-N'-(5-nitro-2-(quinazolin-2-yl)phenyl)propane-1,3-diamine and acridin- 9-yl-(1H-benzoimidazol-5-yl)-amine, inhibiting enzyme activity with IC50 values of 160.3 and 207.01 μM, respectively. It was revealed that these compounds have antibacterial activity against 29 multidrug-resistant strains of S. aureus with MIC values in the ​​range from 78.12 to 312.5 mg/L. Using the methods of hybrid virtual screening and FRET analysis, we have developed 5 inhibitors of S. aureus sortase A, inhibiting the activity of the enzyme by more than 50% at a concentration of 200 µM. The most promising compound - 2-(2-amino-3-chloro-benzoylamino)-benzoic acid has IC50 = 59.7 μM and is selective for sortase A. It was demonstrated that this compound exhibits antibacterial and antibiofilm activity against S. aureus. Product Description popup.authors Chernii Svitlana V. Anatolii R. Syniuhin Larysa V. Pletniova Oleksii V. Borovikov Mykhailo Y. Losytskyi Serhii А. Starosyla Ihor M. Kotei Protopopov Mykola V. Vladyslav M. Sapelkin popup.nrat_date 2023-01-24 Close