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2. Table Of Contents
In brief
01.
Accessing silent
natural product
gene clusters
04.
Introduction
02.
Metagenomics-
driven drug
discovery
05.
Genome-mining
for natural product
BGCs
03.
Combinatorial
biosynthesis
06.

3. In brief Natural products, which have been chosen through billions of years
for their interactions with biomolecules, have been and continue to
be a key source of medications.
However, due to key hurdles such as high rediscovery rates, difficult
isolation, and poor manufacturing titers, pharmaceutical
corporations scaled down their natural product discovery initiatives
in the 1990s in favour of synthetic chemical libraries.
Insights into secondary microbial metabolism afforded by
breakthroughs in DNA sequencing and synthetic biology technology
have inspired several techniques to solve these difficulties.
The purpose of this Original Research Review Article is to offer an
overview of drug development utilizing natural ingredients (1).

4. Introduction
Humans have long recognized microbes' wide repertory of
chemicals as a potential source of medicines.
Prior to the genomic era, most natural product discovery
initiatives had a 'top-down' strategy, with biological materials
being screened for desirable bioactivities, followed by
compound isolation and characterization.
By the 1990s, however, pharmaceutical corporations were
struggling with high rediscovery rates and had de-emphasized
their efforts.
Contd..

5. With the rapid increase of microbial genomic and metagenomic
datasets showing a massive number of biosynthetic gene clusters in
nature, recent advances in genomics have reignited interest in natural
product discovery . Discovering new natural products is exciting and
extremely important in light of today's growing medication resistance
and health issues.

7. Genome-mining for
natural product BGCs With over 30,000 sequenced bacterial genomes already stored in
public archives, the introduction of next-generation sequencing has
substantially sped the sequencing of microbial genomes at
considerably lower costs, resulting in an exponential expansion of
genomic sequencing data.
However, our existing capacity to easily assess and interpret such
massive quantities of data is an obvious obstacle.
This implies identifying possible secondary metabolites BGCs that
encode for new bioactive compounds from microbial genomes for
natural product drug development.
In addition, several genome-mining methods have been developed
for that purpose.

8. Accessing silent natural
product gene clusters
Secondary metabolism is tightly controlled, and the fact that many BGCs
stay "silent" in the laboratory provides a significant difficulty in "activating"
these BGCs and assessing the therapeutic potential of their encoded natural
products.
As metabolic profiling using advanced analytical methods continues to
uncover new compounds that have eluded detection due to low production
yields, the activation of BGCs that are not or inadequately expressed in
laboratory conditions has resulted in the discovery of a diverse range of
natural products with a variety of bioactivities.
The various research methodologies for activating BGC expression are
highlighted below, focusing on natural product discovery.
Contd..

9. Activation of silent BGCs in
native hosts
Variation of growth conditions
and small molecule inducers
Manipulation of regulators
Perturbation of epigenetic
control
Activation of silent BGCs in
heterologous hosts
Direct capturing and
refactoring of gene clusters
Optimization of heterologous
hosts
For further information on the metabolic, route, and genome engineering techniques in native and heterologous host
systems for secondary metabolism, readers are directed to recent reviews.

10. Metagenomics-driven
drug discovery More than 99% of environmental microorganisms have resisted
laboratory cultivation, and this uncultured microbial majority
represents a tremendous chemical treasure trove.
Metagenomics, which involves the direct capture and analysis of
environmental DNA (eDNA), provides culture-independent and
unbiased access to the microbial biosynthetic potential that would
otherwise be overlooked by traditional methods that require the
isolation and cultivation of pure microbial cultures.
This section highlights the technological and conceptual
developments in metagenomics that resulted in identifying novel
natural products from varied environmental niches such as soil,
marine habitats, and the human body (2).

11. Combinatorial biosynthesis
The explosion of BGC sequence data provides vital insights into how
extraordinarily complex natural products comprising huge physiologically
relevant chemical structure space are formed from a small number of basic
building blocks.
BGCs typically encode two types of biosynthetic enzymes: one that creates
important biosynthetic precursors and assembles the core scaffold and
another that derivatizes the scaffolds.
Understanding nature's reasoning for encoding chemical variety will allow
for rational engineering of biosynthetic pathways to produce analogues of
favoured natural product scaffolds or innovative natural product-like
scaffolds that may be difficult to synthesize for New product drug
development chemically.

12. Conclusion
Despite pharmaceutical corporations' mid-1990s reduction in natural product research activities, natural products remain a
crucial source of inspiration for clinical medications .
Natural product research has been revitalized in recent years due to breakthroughs in DNA sequencing,
genomics/metagenomics, synthetic biology, and genome editing technologies. Analyses of microbial genomes and
metagenomes show that humans have only scratched the surface of microorganisms' chemical and functional diversity.
To prioritize and identify relevant BGCs from genomes/metagenomes, predict the structures of their chemical products,
integrate genomics with metabolomic and biological data to identify genotype-chemotype relationships, and prioritize
downstream characterization efforts, bioinformatic tools have been developed.
In addition, new DNA capture and assembly methods and multiplexed genome engineering technologies make it possible to
optimize heterologous expression systems and biosynthetic pathways for secondary metabolite synthesis.
These advancements pave the path for more systematic reviews and focused identification of new natural compounds based
on genetic data (3).

13. Pubrica has experience writing for the medical industry professionally.
Additionally, the team of medical professionals at Pubrica provides
exceptional medical writing services that draw on their backgrounds
in clinical research, pharmacology, public health, regulatory writing
clinical report forms (CRF), biostatistics, psychology, life science,
dentistry, radiology, dermatology, diabetes, gynaecology, cardiology,
biochemistry, forensics, surgery, neurology, psychiatry, genomics,
medical devices, pharmaceutical, nutraceutical, hospitals,
universities, publishers, PhDs.
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