Auroramycin: A Potent Antibiotic from Streptomyces roseosporus by CRISPR-Cas9 Activation

Yee Hwee Lim; Fong Tian Wong; Wan Lin Yeo; Kuan Chieh Ching; Yi Wee Lim; Elena Heng; Shuwen Chen; De Juin Tsai; Tsai Ling Lauderdale; Kak Shan Shia; Ying Swan Ho; Shawn Hoon; Ee Lui Ang; Mingzi M. Zhang; Huimin Zhao

doi:10.1002/cbic.201800266

Auroramycin: A Potent Antibiotic from Streptomyces roseosporus by CRISPR-Cas9 Activation

Yee Hwee Lim, Fong Tian Wong, Wan Lin Yeo, Kuan Chieh Ching, Yi Wee Lim, Elena Heng, Shuwen Chen, De Juin Tsai, Tsai Ling Lauderdale, Kak Shan Shia, Ying Swan Ho, Shawn Hoon, Ee Lui Ang, Mingzi M. Zhang, Huimin Zhao

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

Abstract

Silent biosynthetic gene clusters represent a potentially rich source of new bioactive compounds. We report the discovery, characterization, and biosynthesis of a novel doubly glycosylated 24-membered polyene macrolactam from a silent biosynthetic gene cluster in Streptomyces roseosporus by using the CRISPR-Cas9 gene cluster activation strategy. Structural characterization of this polyketide, named auroramycin, revealed a rare isobutyrylmalonyl extender unit and a unique pair of amino sugars. Relative and absolute stereochemistry were determined by using a combination of spectroscopic analyses, chemical derivatization, and computational analysis. The activated gene cluster for auroramycin production was also verified by transcriptional analyses and gene deletions. Finally, auroramycin exhibited potent anti-methicillin-resistant Staphylococcus aureus (anti-MRSA) activity towards clinical drug-resistant isolates.

Original language	English (US)
Pages (from-to)	1716-1719
Number of pages	4
Journal	ChemBioChem
Volume	19
Issue number	16
DOIs	https://doi.org/10.1002/cbic.201800266
State	Published - Aug 16 2018

Keywords

biosynthesis
genomics
glycosylation
lactams
natural products

ASJC Scopus subject areas

Biochemistry
Molecular Medicine
Molecular Biology
Organic Chemistry

Online availability

10.1002/cbic.201800266

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title = "Auroramycin: A Potent Antibiotic from Streptomyces roseosporus by CRISPR-Cas9 Activation",

abstract = "Silent biosynthetic gene clusters represent a potentially rich source of new bioactive compounds. We report the discovery, characterization, and biosynthesis of a novel doubly glycosylated 24-membered polyene macrolactam from a silent biosynthetic gene cluster in Streptomyces roseosporus by using the CRISPR-Cas9 gene cluster activation strategy. Structural characterization of this polyketide, named auroramycin, revealed a rare isobutyrylmalonyl extender unit and a unique pair of amino sugars. Relative and absolute stereochemistry were determined by using a combination of spectroscopic analyses, chemical derivatization, and computational analysis. The activated gene cluster for auroramycin production was also verified by transcriptional analyses and gene deletions. Finally, auroramycin exhibited potent anti-methicillin-resistant Staphylococcus aureus (anti-MRSA) activity towards clinical drug-resistant isolates.",

keywords = "biosynthesis, genomics, glycosylation, lactams, natural products",

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note = "Funding Information: This work was funded by the NRF BTDA grant (NRF2013-THE001-094, M.M.Z., Y.H.L., F.T.W., E.L.A.) and the A*STAR Visiting Investigator Program (H.Z.) We thank Sydney Brenner (MEL) for his advice and Simon Choo (ICES SCAPAC) for his assistance with the CD measurements. Publisher Copyright: {\textcopyright} 2018 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim",

year = "2018",

month = aug,

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doi = "10.1002/cbic.201800266",

language = "English (US)",

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journal = "ChemBioChem",

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AU - Ching, Kuan Chieh

AU - Lim, Yi Wee

AU - Heng, Elena

AU - Chen, Shuwen

AU - Tsai, De Juin

AU - Lauderdale, Tsai Ling

AU - Shia, Kak Shan

AU - Ho, Ying Swan

AU - Hoon, Shawn

AU - Ang, Ee Lui

AU - Zhang, Mingzi M.

AU - Zhao, Huimin

N1 - Funding Information: This work was funded by the NRF BTDA grant (NRF2013-THE001-094, M.M.Z., Y.H.L., F.T.W., E.L.A.) and the A*STAR Visiting Investigator Program (H.Z.) We thank Sydney Brenner (MEL) for his advice and Simon Choo (ICES SCAPAC) for his assistance with the CD measurements. Publisher Copyright: © 2018 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

PY - 2018/8/16

Y1 - 2018/8/16

N2 - Silent biosynthetic gene clusters represent a potentially rich source of new bioactive compounds. We report the discovery, characterization, and biosynthesis of a novel doubly glycosylated 24-membered polyene macrolactam from a silent biosynthetic gene cluster in Streptomyces roseosporus by using the CRISPR-Cas9 gene cluster activation strategy. Structural characterization of this polyketide, named auroramycin, revealed a rare isobutyrylmalonyl extender unit and a unique pair of amino sugars. Relative and absolute stereochemistry were determined by using a combination of spectroscopic analyses, chemical derivatization, and computational analysis. The activated gene cluster for auroramycin production was also verified by transcriptional analyses and gene deletions. Finally, auroramycin exhibited potent anti-methicillin-resistant Staphylococcus aureus (anti-MRSA) activity towards clinical drug-resistant isolates.

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Auroramycin: A Potent Antibiotic from Streptomyces roseosporus by CRISPR-Cas9 Activation

Abstract

Keywords

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