title: Combinatorial biosynthesis and antibacterial evaluation of glycosylated derivatives of 12-membered macrolide antibiotic YC-17.
abstract: Expression plasmids carrying different deoxysugar biosynthetic gene cassettes and the gene encoding a substrate-flexible glycosyltransferase DesVII were constructed and introduced into Streptomyces venezuelae YJ003 mutant strain bearing a deletion of a desosamine biosynthetic (des) gene cluster. The resulting recombinants produced macrolide antibiotic YC-17 analogs possessing unnatural sugars replacing native D-desosamine. These metabolites were isolated and further purified using chromatographic techniques and their structures were determined as D-quinovosyl-10-deoxymethynolide, L-rhamnosyl-10-deoxymethynolide, L-olivosyl-10-deoxymethynolide, and D-boivinosyl-10-deoxymethynolide on the basis of 1D and 2D NMR and MS analyses and the stereochemistry of sugars was confirmed using coupling constant values and NOE correlations. Their antibacterial activities were evaluated in vitro against erythromycin-susceptible and -resistant Enterococcus faecium and Staphylococcus aureus. Substitution with L-rhamnose displayed better antibacterial activity than parent compound YC-17 containing native sugar D-desosamine. The present study on relationships between chemical structures and antibacterial activities could be useful in generation of novel advanced antibiotics utilizing combinatorial biosynthesis approach.
authors.affiliation: Department of Chemistry and Nano Sciences, Ewha Womans University, Seoul 120-750, Republic of Korea; Institute of Nano-Biotechnology, Ewha Womans University, Seoul 120-750, Republic of Korea.
authors.forename: Pramod B
authors.initials: PB
authors.lastname: Shinde
authors.forename: Ah Reum
authors.initials: AR
authors.lastname: Han
authors.forename: Jaeyong
authors.initials: J
authors.lastname: Cho
authors.forename: So Ra
authors.initials: SR
authors.lastname: Lee
authors.forename: Yeon Hee
authors.initials: YH
authors.lastname: Ban
authors.forename: Young Ji
authors.initials: YJ
authors.lastname: Yoo
authors.forename: Eun Ji
authors.initials: EJ
authors.lastname: Kim
authors.forename: Eunji
authors.initials: E
authors.lastname: Kim
authors.forename: Myoung-Chong
authors.initials: MC
authors.lastname: Song
authors.forename: Je Won
authors.initials: JW
authors.lastname: Park
authors.forename: Dong Gun
authors.initials: DG
authors.lastname: Lee
authors.forename: Yeo Joon
authors.initials: YJ
authors.lastname: Yoon
mesh_terms: D000606:Amino Sugars / Q000378:metabolism; D000900:Anti-Bacterial Agents / Q000096:biosynthesis* / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology*; D016984:Enterococcus faecium / Q000187:drug effects; D005818:Genetic Engineering; D006031:Glycosylation; D018942:Macrolides / Q000737:chemistry* / Q000378:metabolism* / Q000494:pharmacology; D008826:Microbial Sensitivity Tests; D015394:Molecular Structure; D009154:Mutation; D011994:Recombinant Proteins / Q000737:chemistry / Q000378:metabolism; D012210:Rhamnose / Q000378:metabolism; D013211:Staphylococcus aureus / Q000187:drug effects; D013302:Streptomyces / Q000235:genetics / Q000378:metabolism*; D013329:Structure-Activity Relationship
chemical_list: D000606:Amino Sugars; D000900:Anti-Bacterial Agents; D018942:Macrolides; D011994:Recombinant Proteins; C116391:YC-17 macrolide; C110125:desosamine; D012210:Rhamnose
keywords: Combinatorial biosynthesis; Macrolides; Streptomyces venezuelae; YC-17