Chemoenzymatic Synthesis of Glycosylated Macrolactam Analogues of the Macrolide Antibiotic YC-17

Pramod B. Shinde; Hong Se Oh; Hyemin Choi; Kris Rathwell; Yeon Hee Ban; Eun Ji Kim; Inho Yang; Dong Gun Lee; David H. Sherman; Han Young Kang; Yeo Joon Yoon

doi:10.1002/adsc.201500250

Chemoenzymatic Synthesis of Glycosylated Macrolactam Analogues of the Macrolide Antibiotic YC-17

Pramod B. Shinde, Hong Se Oh, Hyemin Choi, Kris Rathwell, Yeon Hee Ban, Eun Ji Kim, Inho Yang, Dong Gun Lee, David H. Sherman, Han Young Kang, Yeo Joon Yoon

Research output: Contribution to journal › Article › peer-review

9 Scopus citations

Abstract

YC-17 is a 12-membered ring macrolide antibiotic produced from Streptomyces venezuelae ATCC 15439 and is composed of the polyketide macrolactone 10-deoxymethynolide appended with D-desosamine. In order to develop structurally diverse macrolactam analogues of YC-17 with improved therapeutic potential, a combined approach involving chemical synthesis and engineered cell-based biotransformation was employed. Eight new antibacterial macrolactam analogues of YC-17 were generated by supplying a novel chemically synthesized macrolactam aglycone to S. venezuelae mutants harboring plasmids capable of synthesizing several unnatural sugars for subsequent glycosylation. Some YC-17 macrolactam analogues were active against erythromycin-resistant bacterial pathogens and displayed improved metabolic stability in vitro. The enhanced therapeutic potential demonstrated by these glycosylated macrolactam analogues reveals the unique potential of chemoenzymatic synthesis in antibiotic drug discovery and development.

Original language	English
Pages (from-to)	2697-2711
Number of pages	15
Journal	Advanced Synthesis and Catalysis
Volume	357
Issue number	12
DOIs	https://doi.org/10.1002/adsc.201500250
State	Published - 1 Aug 2015

Keywords

antibacterial activity
glycosyltransferase
macrolide glycosides
Streptomyces venezuelae
YC-17

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title = "Chemoenzymatic Synthesis of Glycosylated Macrolactam Analogues of the Macrolide Antibiotic YC-17",

abstract = "YC-17 is a 12-membered ring macrolide antibiotic produced from Streptomyces venezuelae ATCC 15439 and is composed of the polyketide macrolactone 10-deoxymethynolide appended with D-desosamine. In order to develop structurally diverse macrolactam analogues of YC-17 with improved therapeutic potential, a combined approach involving chemical synthesis and engineered cell-based biotransformation was employed. Eight new antibacterial macrolactam analogues of YC-17 were generated by supplying a novel chemically synthesized macrolactam aglycone to S. venezuelae mutants harboring plasmids capable of synthesizing several unnatural sugars for subsequent glycosylation. Some YC-17 macrolactam analogues were active against erythromycin-resistant bacterial pathogens and displayed improved metabolic stability in vitro. The enhanced therapeutic potential demonstrated by these glycosylated macrolactam analogues reveals the unique potential of chemoenzymatic synthesis in antibiotic drug discovery and development.",

keywords = "antibacterial activity, glycosyltransferase, macrolide glycosides, Streptomyces venezuelae, YC-17",

author = "Shinde, {Pramod B.} and Oh, {Hong Se} and Hyemin Choi and Kris Rathwell and Ban, {Yeon Hee} and Kim, {Eun Ji} and Inho Yang and Lee, {Dong Gun} and Sherman, {David H.} and Kang, {Han Young} and Yoon, {Yeo Joon}",

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year = "2015",

month = aug,

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doi = "10.1002/adsc.201500250",

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AU - Shinde, Pramod B.

AU - Oh, Hong Se

AU - Choi, Hyemin

AU - Rathwell, Kris

AU - Ban, Yeon Hee

AU - Kim, Eun Ji

AU - Yang, Inho

AU - Lee, Dong Gun

AU - Sherman, David H.

AU - Kang, Han Young

AU - Yoon, Yeo Joon

PY - 2015/8/1

Y1 - 2015/8/1

N2 - YC-17 is a 12-membered ring macrolide antibiotic produced from Streptomyces venezuelae ATCC 15439 and is composed of the polyketide macrolactone 10-deoxymethynolide appended with D-desosamine. In order to develop structurally diverse macrolactam analogues of YC-17 with improved therapeutic potential, a combined approach involving chemical synthesis and engineered cell-based biotransformation was employed. Eight new antibacterial macrolactam analogues of YC-17 were generated by supplying a novel chemically synthesized macrolactam aglycone to S. venezuelae mutants harboring plasmids capable of synthesizing several unnatural sugars for subsequent glycosylation. Some YC-17 macrolactam analogues were active against erythromycin-resistant bacterial pathogens and displayed improved metabolic stability in vitro. The enhanced therapeutic potential demonstrated by these glycosylated macrolactam analogues reveals the unique potential of chemoenzymatic synthesis in antibiotic drug discovery and development.

AB - YC-17 is a 12-membered ring macrolide antibiotic produced from Streptomyces venezuelae ATCC 15439 and is composed of the polyketide macrolactone 10-deoxymethynolide appended with D-desosamine. In order to develop structurally diverse macrolactam analogues of YC-17 with improved therapeutic potential, a combined approach involving chemical synthesis and engineered cell-based biotransformation was employed. Eight new antibacterial macrolactam analogues of YC-17 were generated by supplying a novel chemically synthesized macrolactam aglycone to S. venezuelae mutants harboring plasmids capable of synthesizing several unnatural sugars for subsequent glycosylation. Some YC-17 macrolactam analogues were active against erythromycin-resistant bacterial pathogens and displayed improved metabolic stability in vitro. The enhanced therapeutic potential demonstrated by these glycosylated macrolactam analogues reveals the unique potential of chemoenzymatic synthesis in antibiotic drug discovery and development.

KW - antibacterial activity

KW - glycosyltransferase

KW - macrolide glycosides

KW - Streptomyces venezuelae

KW - YC-17

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DO - 10.1002/adsc.201500250

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VL - 357

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JO - Advanced Synthesis and Catalysis

JF - Advanced Synthesis and Catalysis

IS - 12

ER -

Chemoenzymatic Synthesis of Glycosylated Macrolactam Analogues of the Macrolide Antibiotic YC-17

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