Nature: Discover new natural products at an unprecedented rate

Many of the drugs we use in modern medicine are produced
naturally by microorganisms.
Penicillin, an antibiotic extracted from certain molds, is one of the best-known natural products because it is considered one of
the greatest advances in medicine and human health.
As DNA sequencing becomes cheaper and faster, scientists now have access to hundreds of thousands of microbial genomes and the natural products
they produce.
However, Doug Mitchell (MMG), the John and Margaret Witt Professor of Chemistry at the University of Illinois, says that pales in comparison to the amount of compounds these organisms can produce using the genetic pathways they possess
.

"This is just the tip of
the iceberg.
There is a gap
between what we know today and what nature is capable of producing.
At least 100 to 1
.
”

A group of natural products have become a popular source of antibiotics, known as ribosome synthesis and posttranslational modified peptides, or simply RiPPs
.
Traditional methods of obtaining RiPPs are slow and involve taking genes one by one and putting them into model organisms, such as E.
coli, to see what compounds
it produces.
However, in a new paper resulting from a large-scale collaboration at the Carl R.
Woese Institute for Genomic Biology, researchers were able to discover and characterize new RiPPs at an unprecedented speed and scale, using Illinois Biocasting Advanced Biofabrication
.
iBioFAB is a laboratory automation system that can evaluate and assemble multiple synthetic gene pathways of hundreds of genes at once, which traditionally takes many researchers and more time to complete
。 The project was a collaboration between Mitchell's lab, Huimin Zhao's (BSD/GSE-led/CABBI/CGD/MMG), the lab of the Steven L.
Miller Chair in Chemical and Biomolecular Engineering, the lab of Wilfred van der Donk (MMG), the Richard E.
Heckert Chair in Chemistry, and the Howard Hughes Institute of Medical Research
。

Three co-first authors, Alex Battiste, a fourth-year PhD student in Mitchell's lab, Shi Chengyou, a fifth-year PhD student in Zhao's lab, and Richard Ayikpoe, a postdoc in van der Donk's lab, describe how they led part of the
project in their respective labs.
Professor Shi's team sequenced the synthetic genes and then assembled them into candidate pathways or clusters of genes using iBioFAB integrated with a genome mining program called RODEO
.
The different types of gene clusters were then handed over to Battiste and Ayikpoe's team to test which pathways were functional and could potentially produce new RiPPs for E.
coli.
Any RiPPs structure that showed antibiotic activity was described
in detail by Ayikpoe's team.
This high-throughput technique allows 96 pathways containing about 400 genes to be tested simultaneously, yielding 30 new compounds
.

"Compared to traditional RiPP discovery methods, our platform is scalable and high-throughput in many ways, from the identification, cloning, production, detection, and characterization of biosynthetic gene clusters," Shi said
.
"I would say that this is the first platform
to discover RiPP on a large scale.
"

Of the new compounds discovered, three were found to have antimicrobial properties
.
When tested for Klebsiella pneumoniae, a highly virulent antibiotic-resistant bacterium, the newly discovered antimicrobial RiPPs can effectively kill this dangerous bacteria
.
The researchers say this could be a new way to discover compounds that can effectively fight bacteria
that are resistant to current antibiotic drugs.

"We identified three RiPPs that have antimicrobial properties
against known pathogens of hospital-acquired infections, including Klebsiella," Ayikpoe said.
"This study shows that by using this platform to expand the number of biosynthetic gene clusters that we can screen for at once, we are more likely to find antimicrobial compounds
with therapeutic properties.
"

The team says the paper's goals are twofold: to demonstrate the ability of high-throughput techniques to rapidly construct and test gene clusters of new RiPPs, and to highlight possible large-scale collaborative projects
within the IGB.
"It's impossible for any of our labs to do all of this
alone.
IGBs provide a melting pot for this interdisciplinary research," Mitchell said
.

Battiste describes how IGB naturally inspires collaborative projects
like this one through its design.
"IGB makes it easy to see them in your theme, which lowers the barrier to
starting projects with them," Battiste says.
"Everyone on the MMG theme is doing similar things, even if we come from different labs
.
So we all have different types of expertise, but they all fit together very well and you can get an idea of the type of
technology they use.
It's one of my favorite parts of working here, the sense
of camaraderie between everyone on the team.
”

To highlight the collaborative spirit embodied in their papers, the labs are working with the Department of Chemistry to produce a video showcasing all their research and IGB support for this type of project and hopefully inspire more such projects
.
This video will be released
soon with the publication of the paper.
   

All three co-first authors describe how their education, research and employment prospects at IGB have benefited greatly from their time at IGB, highlighting that IGB's talent and technology work together to make it a great place to
conduct research.
"In terms of scientific and social life, the atmosphere of cooperation offered by IGB in terms of diversity and development is really remarkable
.
" Ayikpoe said
.

The research was funded
by the NIH.