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

Ah Reum Han, Pramod B. Shinde, Je Won Park, Jaeyong Cho, So Ra Lee, Yeon Hee Ban, Young Ji Yoo, Eun Ji Kim, Eunji Kim, Sung Ryeol Park, Byung Gee Kim, Dong Gun Lee, Yeo Joon Yoon

Research output: Contribution to journalArticle

18 Citations (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.

Original languageEnglish
Pages (from-to)1147-1156
Number of pages10
JournalApplied Microbiology and Biotechnology
Volume93
Issue number3
DOIs
Publication statusPublished - 2012 Feb 1
Externally publishedYes

Fingerprint

Macrolides
Erythromycin
Polyketides
Rhamnose
Enterococcus faecium
Glycosyltransferases
Streptomyces
Structure-Activity Relationship
Multigene Family
Thymidine
Genes
Staphylococcus aureus
Mass Spectrometry
Plasmids
Magnetic Resonance Spectroscopy
narbomycin
Anti-Bacterial Agents
Enzymes
desosamine

Keywords

  • Antibacterial activity
  • Glycosylation
  • Macrolide
  • Narbomycin
  • Streptomyces venezuelae

ASJC Scopus subject areas

  • Biotechnology
  • Applied Microbiology and Biotechnology

Cite this

Engineered biosynthesis of glycosylated derivatives of narbomycin and evaluation of their antibacterial activities. / Han, Ah Reum; Shinde, Pramod B.; Park, Je Won; Cho, Jaeyong; Lee, So Ra; Ban, Yeon Hee; Yoo, Young Ji; Kim, Eun Ji; Kim, Eunji; Park, Sung Ryeol; Kim, Byung Gee; Lee, Dong Gun; Yoon, Yeo Joon.

In: Applied Microbiology and Biotechnology, Vol. 93, No. 3, 01.02.2012, p. 1147-1156.

Research output: Contribution to journalArticle

Han, AR, Shinde, PB, Park, JW, Cho, J, Lee, SR, Ban, YH, Yoo, YJ, Kim, EJ, Kim, E, Park, SR, Kim, BG, Lee, DG & Yoon, YJ 2012, 'Engineered biosynthesis of glycosylated derivatives of narbomycin and evaluation of their antibacterial activities', Applied Microbiology and Biotechnology, vol. 93, no. 3, pp. 1147-1156. https://doi.org/10.1007/s00253-011-3592-9
Han, Ah Reum ; Shinde, Pramod B. ; Park, Je Won ; Cho, Jaeyong ; Lee, So Ra ; Ban, Yeon Hee ; Yoo, Young Ji ; Kim, Eun Ji ; Kim, Eunji ; Park, Sung Ryeol ; Kim, Byung Gee ; Lee, Dong Gun ; Yoon, Yeo Joon. / Engineered biosynthesis of glycosylated derivatives of narbomycin and evaluation of their antibacterial activities. In: Applied Microbiology and Biotechnology. 2012 ; Vol. 93, No. 3. pp. 1147-1156.
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