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Towards safer aminogrycoside antibiotics: structure, function and engineering studies of key biosynthetic enzymes

Abstract

Aminoglycosides are antibiotcs which have a core moiety and various unusual sugars, such as aminosugars and desoxysugars that together with their functional groups are essential for its antibiotic activity, which is the inhibition of protein synthesis due to the interaction with the 305 subunit of bacterial ribosome. Although their toxic effects, aminoglicoside antibiotics are largely precribed in the medicine for the treatment of infectious diseases. Our research group, together with the Group of Prof. Peter Leadlay, Department of Biochemistry of University of Cambridge-UK are studying various enzimes of the biosynthesis of several aminoglycosides, such as gentamycin e sisomicin. Most of these enzymes have completely absence of structural and functional studies in vitro and in vivo and their functions are hypothetic and based only in the analysis of sequencial homology. Also, these biosynthetic pathways have peculiarities that may be explored in combinatorial biosynthesis to generate new derivatives of aminoglycosides which may have altered biological activities. Preliminary various genes of these biosynthesis pathway have been cloned, their kinetic activities were characterized by Peter Leadlay group and crystallographic and other biophysical studies are being carried on by our laboratory, which has at least two enzymes have been crystallized and the structure will be solved my experimental phases due to the low similarity with any other structure. The possibility of mobilization of both research groups might strongaly contribute to a multidiciplinary formation for researchers of both sides in the process of investigation of biosynthesis and development of new antibiotics. This will also allow the exchange of knowleage of biophysic techniques, kinetic characterization and genetics and molecular biology of Streptomyces. (AU)

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Scientific publications
(References retrieved automatically from Web of Science and SciELO through information on FAPESP grants and their corresponding numbers as mentioned in the publications by the authors)
DE ARAUJO, NATALIA CERRONE; BURY, PRISCILA DOS SANTOS; TAVARES, MAURICIO TEMOTHEO; HUANG, FANGLU; PARISE-FILHO, ROBERTO; LEADLAY, PETER; BERTACINE DIAS, MARCIO VINICIUS. Crystal Structure of GenD2, an NAD-Dependent Oxidoreductase Involved in the Biosynthesis of Gentamicin. ACS Chemical Biology, v. 14, n. 5, p. 925-933, MAY 2019. Web of Science Citations: 0.
BURY, PRISCILA DOS SANTOS; HUANG, FANGLU; LI, SICONG; SUN, YUHUI; LEADLAY, PETER F.; BERTACINE DIAS, MARCIO VINICIUS. Structural Basis of the Selectivity of GenN, an Aminoglycoside N-Methyltransferase Involved in Gentamicin Biosynthesis. ACS Chemical Biology, v. 12, n. 11, p. 2779-2787, NOV 2017. Web of Science Citations: 2.

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