Driving bacteria to produce potential antibiotic, antiparasitic
compounds

Date:
June 25, 2020
Source:
University of Illinois at Urbana-Champaign, News Bureau
Summary:
Researchers have developed a method to spur the production of new
antibiotic or antiparasitic compounds hiding in the genomes of
actinobacteria, which are the source of the drugs actinomycin and
streptomycin and are known to harbor other untapped chemical riches.



FULL STORY ========================================================================== [Bacteria illustration | Credit: (c) Paulista / stock.adobe.com] Bacteria illustration (stock image).

Credit: (c) Paulista / stock.adobe.com [Bacteria illustration | Credit:
(c) Paulista / stock.adobe.com] Bacteria illustration (stock image).

Credit: (c) Paulista / stock.adobe.com Close Researchers have developed
a method to spur the production of new antibiotic or antiparasitic
compounds hiding in the genomes of actinobacteria, which are the source
of drugs such as actinomycin and streptomycin and are known to harbor
other untapped chemical riches. The scientists report their findings in
the journal eLife.


==========================================================================
The researchers wanted to overcome a decades-old problem that confronts
those hoping to study and make use of the countless antibiotic, antifungal
and antiparasitic compounds that bacteria can produce, said Satish Nair,
a University of Illinois at Urbana-Champaign professor of biochemistry
who led the research.

"In laboratory conditions, bacteria don't make the number of molecules
they have the capability of making," he said. "And that's because many
are regulated by small-molecule hormones that aren't produced unless
the bacteria are under threat." Nair and his colleagues wanted to
determine how such hormones influence the production of antibiotics
in actinobacteria. By exposing their bacteria to the right hormone or combination of hormones, the researchers hope to spur the microbes to
produce new compounds that are medically useful.

The team focused on avenolide, a hormone that is more chemically
stable than one used in earlier studies of bacterial hormones. Avenolide regulates the production of an antiparasitic compound known as avermectin
in a soil microbe.

A chemically modified version of this compound, ivermectin, is used as
a treatment for river blindness, a disease transmitted by flies that
blinded millions of people, mostly in sub-Saharan Africa, before the
drug was developed.

For the new study, chemistry graduate student Iti Kapoor developed a
more streamlined process for synthesizing avenolide in the lab than
was previously available. This allowed the team to study the hormone's interactions with its receptor both inside and outside bacterial cells.

"Using a method called X-ray crystallography, Iti and biochemistry
graduate student Philip Olivares were able to determine how the hormone
binds to its receptor and how the receptor binds to the DNA in the absence
of hormones," Nair said. "Typically, these receptors sit on the genome
and they basically act as brakes." The researchers discovered that
when the hormone binds to it, the receptor loses its ability to cling
to DNA. This turns off the brakes, allowing the organism to churn out
defensive compounds like antibiotics.

Knowing which regions of the receptor are involved in binding to the
hormone and to the DNA enabled the team to scan the genomes of dozens
of actinobacteria to find sequences that had the right traits to bind
to their receptor or to similar receptors. This process, called genome
mining, allowed the team to identify 90 actinobacteria that appear to
be regulated by avenolide or other hormones in the same class.

"Our long-term project is to take those 90 bacteria, grow them up in
the laboratory, add chemically synthesized hormones to them and see
what new molecules are being produced," Nair said. "The beauty of our
approach is that we can now get the bacteria to produce large quantities
of molecules that normally we would not be able to make in the lab."
Some of these new compounds are likely to have medical relevance, he said.


========================================================================== Story Source: Materials provided by University_of_Illinois_at_Urbana-Champaign,_News_Bureau.

Original written by Diana Yates. Note: Content may be edited for style
and length.


========================================================================== Journal Reference:
1. Iti Kapoor, Philip Olivares, Satish K Nair. Biochemical basis
for the
regulation of biosynthesis of antiparasitics by bacterial hormones.

eLife, 2020; 9 DOI: 10.7554/eLife.57824 ==========================================================================

Link to news story: https://www.sciencedaily.com/releases/2020/06/200625122735.htm

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