Structural insights into the function of aminoglycoside-resistance A1408 16S rRNA methyltransferases from antibiotic-producing and human pathogenic bacteria

X-ray crystal structures were determined of the broad-spectrum aminoglycoside-resistance A1408 16S rRNA methyltransferases KamB and NpmA, from the aminoglycoside-producer Streptoalloteichus tenebrarius and human pathogenic Escherichia coli, respectively. Consistent with their common function, both are Class I methyltransferases with additional highly conserved structural motifs that embellish the core SAM-binding fold. In overall structure, the A1408 rRNA methyltransferase were found to be most similar to a second family of Class I methyltransferases of distinct substrate specificity (m7G46 tRNA). Critical residues for A1408 rRNA methyltransferase activity were experimentally defined using protein mutagenesis and bacterial growth assays with kanamycin. Essential residues for SAM coenzyme binding and an extended protein surface that likely interacts with the 30S ribosomal subunit were thus revealed. The structures also suggest potential mechanisms of A1408 target nucleotide selection and positioning. We propose that a dynamic extended loop structure that is positioned adjacent to both the bound SAM and a functionally critical structural motif may mediate concerted conformational changes in rRNA and protein that underpin the specificity of target selection and activation of methyltransferase activity. These new structures provide important new insights that may provide a starting point for strategies to inhibit these emerging causes of pathogenic bacterial resistance to aminoglycosides

AI is a viable alternative to high throughput screening: a 318-target study

: High throughput screening (HTS) is routinely used to identify bioactive small molecules. This requires physical compounds, which limits coverage of accessible chemical space. Computational approaches combined with vast on-demand chemical libraries can access far greater chemical space, provided that the predictive accuracy is sufficient to identify useful molecules. Through the largest and most diverse virtual HTS campaign reported to date, comprising 318 individual projects, we demonstrate that our AtomNet® convolutional neural network successfully finds novel hits across every major therapeutic area and protein class. We address historical limitations of computational screening by demonstrating success for target proteins without known binders, high-quality X-ray crystal structures, or manual cherry-picking of compounds. We show that the molecules selected by the AtomNet® model are novel drug-like scaffolds rather than minor modifications to known bioactive compounds. Our empirical results suggest that computational methods can substantially replace HTS as the first step of small-molecule drug discovery

THE CHARACTERISTIC OF THE NEW SITE-SPECIFIC ENDONUCLEASES AND METHYLASES FROM STRAINS BACILLUS SPECIES IS4, BACILLUS SPECIES ST5 AND ACINETOBACTER SPECIES M

The purpose of the work: isolation of the ferments of systems modification-restriction, its characteristic and search for the new producers of site-specific endonucleases. The new site-specific endonucleases and methyltranspherases have been detected. The detected ferments can be used in the gene engineering, molecular-biological investigations of DNA and protein-nucleic recognition. The results can be widely used in cloning the DNA, mapping and determination of primery structure of the DNAAvailable from VNTIC / VNTIC - Scientific & Technical Information Centre of RussiaSIGLERURussian Federatio

Research of the environmentally safe waste-based building materials

Introduction: in the article the estimation of new ecological safety biopositive polymer-mineral composite (BPMC) building materials obtained with the use of technogenic wastes is considered. This approach is one of the ways to solve the problem of improving the environmental safety of the environment. Materials and methods: BMPC environmental safety studies were performed using microstructural, X-ray and elemental analysis methods, studying physical and mechanical properties and fire safety. Man-caused wastes inventory and classificational ecological assessment by the lif e cycle was carried out. Results: the conformity of the Baikal region man-caused wastes (such as fly ash from heat-power engineering, aluminosilicate microspheres, isolated from bottom ash wastes, marble dust (microcalcite), industrial waste of polyvinylchloride (PVC), as well as small-sized mica waste in the form of vermiculite) to the basic characteristics that allow to use this wastes in the production of BMPC-products by extrusion as fillers. The man-caused wastes ecological utilization mechanism was developed. Composition of composite materials, in which industrial PVC waste is used as the matrix, and fly ash, ash microspheres, marble dust and vermiculite as fillers, were developed. The proposed technology for the production of BPMC products allows the use of technogenic wastes in a wide range in the composition from 20 to 60 %. The new biopozitive polymer-mineral composite products properties were studied. Conclusions: the conducted studies of the composition and properties of samples obtained using different types of man-made waste in the polymer-mineral composites production proved that the production of BPMC products ensures the building materials and environmental safety through the reliable and durable materials production that comply with regulatory requirements. According to the life cycle environmental safety assessment, the waste products obtained on the basis of waste have significant advantages in terms of a technical and environmental characteristics set

Intravenous Nicotinamide Riboside Administration Has a Cardioprotective Effect in Chronic Doxorubicin-Induced Cardiomyopathy

Doxorubicin, which is widely used to treat a broad spectrum of malignancies, has pronounced dose-dependent side effects leading to chronic heart failure development. Nicotinamide riboside (NR) is one of the promising candidates for leveling the cardiotoxic effect. In the present work, we performed a comparative study of the cardioprotective and therapeutic actions of various intravenous NR administration modes in chronic doxorubicin-induced cardiomyopathy in Wistar rats. The study used 60 mature male SPF Wistar rats. The animals were randomized into four groups (a control group and three experimental groups) which determined the doxorubicin (intraperitoneally) and NR (intravenous) doses as well as the specific modes of NR administration (combined, preventive). We demonstrated the protective effect of NR on the cardiovascular system both with combined and preventive intravenous drug administration, which was reflected in a fibrous tissue formation decrease, reduced fractional-shortening decrease, and better antioxidant system performance. At the same time, it is important to note that the preventive administration of NR had a more significant protective effect on the animal organism as a whole. This was confirmed by better physical activity parameters and vascular bed conditions. Thus, the data obtained during the study can be used for further investigation into chronic doxorubicin-induced cardiomyopathy prevention and treatment approaches