Differentiating strong antibiotic producers from weaker ones

Date:
July 30, 2021
Source:
Washington University in St. Louis
Summary:
Biologists are using comparative metabologenomics to try to
uncover what may be 'silencing' Streptomyces and preventing it
from producing desirable compounds encoded by its genes.



FULL STORY ==========================================================================
An untapped trove of desirable drug-like molecules is hidden in the
genomes of Streptomyces bacteria -- the same bacteria responsible for
the first bacterial antibiotics to treat tuberculosis back in the 1940s.


========================================================================== Isolating them, however, has proved challenging. Now, biologists at
Washington University in St. Louis are using comparative metabologenomics
to try to uncover what may be "silencing" Streptomyces and preventing
it from producing desirable compounds encoded by its genes.

"We examined genetic differences across the genomes of Streptomyceswhile
at the same time looking at antibiotic outputs," said Joshua Blodgett, assistant professor of biology in Arts & Sciences, the corresponding
author of research published in the Proceedings of the National Academy
of Sciences (PNAS). "This study highlights comparative metabologenomics
as a powerful approach to expose the features that differentiate strong antibiotic producers from weaker ones." Blodgett's team, including
recent PhD graduate Yunci Qi and postdoctoral research associate Keshav
Nepal, compared a group of antibiotic-producing strains of Streptomyces
and other nonproducing or poor-producing strains to reveal genomic
differences that could affect drug production.

The researchers found a few key differences between the strains. Notably,
the good producers of polycyclic tetramate macrolactam (PTM) antibiotics
seemed to benefit from griseorhodin production, which the researchers
did not anticipate and originally had tried to eliminate.

But a handful of nucleotides matter, too. Metabologenomics revealed
that the presence or absence of two to three nucleotides -- essentially
letters that make up a genetic message -- can tune the switches that
drive PTM antibiotic production. This type of fine control previously
had been found in certain bacteria that cause disease, but largely had
been overlooked in bacteria that produce drugs.

"Our work highlights the problem of silent gene clusters and the need
to understand them for next-generation drug discovery," Blodgett said.

"Comparative metabologenomics is a generally
adoptable strategy, and we hope that others might
use it to examine their own strains and drug pathways." ========================================================================== Story Source: Materials provided by
Washington_University_in_St._Louis. Note: Content may be edited for
style and length.


========================================================================== Journal Reference:
1. Yunci Qi, Keshav K. Nepal, Joshua A. V. Blodgett. A comparative
metabologenomic approach reveals mechanistic insights
into Streptomyces antibiotic crypticity. Proceedings of the
National Academy of Sciences, 2021; 118 (31): e2103515118 DOI:
10.1073/pnas.2103515118 ==========================================================================

Link to news story: https://www.sciencedaily.com/releases/2021/07/210729183632.htm

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