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Heterologous expression-facilitated natural products’ discovery in actinomycetes

  • Min Xu
  • Gerard D. WrightEmail author
Natural Products - Original Paper

Abstract

Actinomycetes produce many of the drugs essential for human and animal health as well as crop protection. Genome sequencing projects launched over the past two decades reveal dozens of cryptic natural product biosynthetic gene clusters in each actinomycete genome that are not expressed under regular laboratory conditions. This so-called ‘chemical dark matter’ represents a potentially rich untapped resource for drug discovery in the genomic era. Through improved understanding of natural product biosynthetic logic coupled with the development of bioinformatic and genetic tools, we are increasingly able to access this ‘dark matter’ using a wide variety of strategies with downstream potential application in drug development. In this review, we discuss recent research progress in the field of cloning of natural product biosynthetic gene clusters and their heterologous expression in validating the potential of this methodology to drive next-generation drug discovery.

Keywords

Natural products Streptomyces Heterologous expression Drug discovery 

Abbreviations

attB/attP

Attachment site of bacteria/phage

BAC

Bacterial artificial chromosome

BGC

Biosynthetic gene cluster

CATCH

Cas9-assisted targeting of chromosome segment

CRISPR

Clustered regularly interspaced short palindromic repeats

DiPac

Direct pathway cloning

DSB

Double strand break

eDNA

Environmental DNA

ExoCET

Exonuclease in vitro assembly combined with RecET

5-FOA

5-Fluoroorotic acid

HEx

Heterologous expression

HMW

High molecular weight

ISR

Integrase-mediated site-specific recombination

LCHR

Linear–circular homologous recombination

LLHR

Linear–linear homologous recombination

mCRISTA

Multiplexed CRISPR/Cas9- and TAR-mediated promoter engineering

NHEJ

Non-homologous end joining

NP

Natural product

NRP

Nonribosomal peptide

NRPS

Nonribosomal peptide synthetase

PAC

Phage P1 artificial chromosome

PCR

Polymerase chain reaction

PK

Polyketide

PKS

Polyketide synthetase

PPTase

Phosphopantetheinyl transferase

PTM

Polycyclic tetramate macrolactam

RiPPs

Ribosomally synthesized and post-translationally modified peptides

SARP

Streptomyces antibiotics regulatory protein

TAR

Transformation-associated recombination

TSS

Transcription start site

Notes

Acknowledgements

We thank Dr. Grace Yim and Elizabeth Culp for critical reading and discussion of the manuscript and Christy Groves for assistance in the preparation of Fig. 3. The authors gratefully acknowledge funding from the Canadian Institutes of Health Research (MT-14981), the Bill and Melinda Gates Foundation, and the Ontario Research Fund. G. D. W. is supported by a Canada Research Chair.

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Copyright information

© Society for Industrial Microbiology and Biotechnology 2018

Authors and Affiliations

  1. 1.M.G. DeGroote Institute for Infectious Disease Research, Department of Biochemistry and Biomedical SciencesDeGroote School of Medicine, McMaster UniversityHamiltonCanada

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