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Engineered biosynthesis of glycosylated derivatives of narbomycin and evaluation of their antibacterial activities

Title
Engineered biosynthesis of glycosylated derivatives of narbomycin and evaluation of their antibacterial activities
Authors
Han A.R.Shinde P.B.Park J.W.Cho J.Lee S.R.Ban Y.H.Yoo Y.J.Kim E.J.Kim E.Park S.R.Kim B.-G.Lee D.G.Yoon Y.J.
Ewha Authors
윤여준Pramod B. Shinde
SCOPUS Author ID
윤여준scopus
Issue Date
2012
Journal Title
Applied Microbiology and Biotechnology
ISSN
0175-7598JCR Link
Citation
vol. 93, no. 3, pp. 1147 - 1156
Indexed
SCI; SCIE; SCOPUS WOS scopus
Abstract
A 14-membered macrolide antibiotic narbomycin produced from Streptomyces venezuelae ATCC 15439 is composed of polyketide macrolactone ring and D-desosamine as a deoxysugar moiety, which acts as an important determinant of its antibacterial activity. In order to generate diverse glycosylated derivatives of narbomycin, expression plasmids carrying different deoxysugar biosynthetic gene cassettes and the gene encoding a substrate-flexible glycosyltransferase DesVII were constructed and introduced into S. venezuelae YJ003 mutant strain bearing a deletion of thymidine-5′-diphospho-D- desosamine biosynthetic gene cluster. The resulting recombinants of S. venezuelae produced a range of new analogs of narbomycin, which possess unnatural sugar moieties instead of native deoxysugar D-desosamine. The structures of narbomycin derivatives were determined through nuclear magnetic resonance spectroscopy and mass spectrometry analyses and their antibacterial activities were evaluated in vitro against erythromycin-susceptible and -resistant Enterococcus faecium and Staphylococcus aureus. Substitution with L-rhamnose or 3-O-demethyl-D-chalcose was demonstrated to exhibit greater antibacterial activity than narbomycin and the clinically relevant erythromycin. This work provides new insight into the functions of deoxysugar biosynthetic enzymes and structure-activity relationships of the sugar moieties attached to the macrolides and demonstrate the potential of combinatorial biosynthesis for the generation of new macrolides carrying diverse sugars with increased antibacterial activities. © 2011 Springer-Verlag.
DOI
10.1007/s00253-011-3592-9
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자연과학대학 > 화학·나노과학전공 > Journal papers
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