Faculty Opinions recommendation of Epigenetic genome mining of an endophytic fungus leads to the pleiotropic biosynthesis of natural products.

Cyanobacteria are prolific producers of natural products and genome mining has shown that many orphan biosynthetic gene clusters can be found in sequenced cyanobacterial genomes. New tools and methodologies are required to investigate these biosynthetic gene clusters and here we present the use of <i>Anabaena </i>sp. strain PCC 7120 as a host for combinatorial biosynthesis of natural products using the indolactam natural products (lyngbyatoxin A, pendolmycin, and teleocidin B-4) as a test case. We were able to successfully produce all three compounds using codon optimized genes from Actinobacteria. We also introduce a new plasmid backbone based on the native <i>Anabaena</i>7120 plasmid pCC7120ζ and show that production of teleocidin B-4 can be accomplished using a two-plasmid system, which can be introduced by co-conjugation.

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Biosynthetic pathways and enzymes involved in the production of phosphonic acid natural products

Bioscience Biotechnology and Biochemistry ◽

10.1093/bbb/zbaa052 ◽

2021 ◽

Vol 85 (1) ◽

pp. 42-52

Author(s):

Taro Shiraishi ◽

Tomohisa Kuzuyama

Keyword(s):

Natural Products ◽

Biosynthetic Pathway ◽

Organophosphorus Compounds ◽

Genome Mining ◽

Biological Molecules ◽

Antibacterial Drug ◽

Gene Encoding ◽

Quarter Century ◽

Lead Compounds ◽

Biosynthetic Machinery

Abstract Phosphonates are organophosphorus compounds possessing a characteristic C−P bond in which phosphorus is directly bonded to carbon. As phosphonates mimic the phosphates and carboxylates of biological molecules to potentially inhibit metabolic enzymes, they could be lead compounds for the development of a variety of drugs. Fosfomycin (FM) is a representative phosphonate natural product that is widely used as an antibacterial drug. Here, we review the biosynthesis of FM, which includes a recent breakthrough to find a missing link in the biosynthetic pathway that had been a mystery for a quarter-century. In addition, we describe the genome mining of phosphonate natural products using the biosynthetic gene encoding an enzyme that catalyzes C–P bond formation. We also introduce the chemoenzymatic synthesis of phosphonate derivatives. These studies expand the repertoires of phosphonates and the related biosynthetic machinery. This review mainly covers the years 2012-2020.

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Recent Advances in Discovery of Lead Structures from Microbial Natural Products: Genomics- and Metabolomics-Guided Acceleration

Molecules ◽

10.3390/molecules26092542 ◽

2021 ◽

Vol 26 (9) ◽

pp. 2542

Author(s):

Linda Sukmarini

Keyword(s):

Natural Products ◽

Genome Mining ◽

Screening Methods ◽

Technological Advancement ◽

Natural Origin ◽

Drug Discovery And Development ◽

New Methodologies ◽

Analytical Instrumentation ◽

Microbial Natural Products ◽

Drug Leads

Natural products (NPs) are evolutionarily optimized as drug-like molecules and remain the most consistently successful source of drugs and drug leads. They offer major opportunities for finding novel lead structures that are active against a broad spectrum of assay targets, particularly those from secondary metabolites of microbial origin. Due to traditional discovery approaches’ limitations relying on untargeted screening methods, there is a growing trend to employ unconventional secondary metabolomics techniques. Aided by the more in-depth understanding of different biosynthetic pathways and the technological advancement in analytical instrumentation, the development of new methodologies provides an alternative that can accelerate discoveries of new lead-structures of natural origin. This present mini-review briefly discusses selected examples regarding advancements in bioinformatics and genomics (focusing on genome mining and metagenomics approaches), as well as bioanalytics (mass-spectrometry) towards the microbial NPs-based drug discovery and development. The selected recent discoveries from 2015 to 2020 are featured herein.

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The Tripod for Bacterial Natural Product Discovery: Genome Mining, Silent Pathway Induction, and Mass Spectrometry-Based Molecular Networking

mSystems ◽

10.1128/msystems.00160-17 ◽

2018 ◽

Vol 3 (2) ◽

Cited By ~ 14

Author(s):

Daniela B. B. Trivella ◽

Rafael de Felicio

Keyword(s):

Mass Spectrometry ◽

Natural Products ◽

Natural Product ◽

Biosynthetic Pathway ◽

Genome Mining ◽

Chemical Compounds ◽

Gene Clusters ◽

Tandem Mass ◽

Molecular Networking ◽

Natural Product Discovery

ABSTRACT Natural products are the richest source of chemical compounds for drug discovery. Particularly, bacterial secondary metabolites are in the spotlight due to advances in genome sequencing and mining, as well as for the potential of biosynthetic pathway manipulation to awake silent (cryptic) gene clusters under laboratory cultivation. Further progress in compound detection, such as the development of the tandem mass spectrometry (MS/MS) molecular networking approach, has contributed to the discovery of novel bacterial natural products. The latter can be applied directly to bacterial crude extracts for identifying and dereplicating known compounds, therefore assisting the prioritization of extracts containing novel natural products, for example. In our opinion, these three approaches—genome mining, silent pathway induction, and MS-based molecular networking—compose the tripod for modern bacterial natural product discovery and will be discussed in this perspective.

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