YSM Issue 93.2

VS.
SCIENCE
THE APOCALYPSE
ANTIBIOTIC
RESISTANCE
BY VICTORIA
VERA
IMAGE COURTESY OF WIKIMEDIA COMMONS
Since the discovery of penicillin, the first commercialized
antibiotic, in 1928, our society has dramatically improved.
We have raised life expectancy, improved quality of life,
and altogether created a healthier world. However, it’s not just
us who have adapted. Bacteria have entered a new age as well,
one characterized by increasing resistance to the antibiotics we
create. Antibiotic resistance was first observed in 1947, around
six years after commercial production of penicillin began. Since
then, the problem has become much more widespread. This poses
a scary new problem for us. In the future, might it be possible
for an infected piercing or scrape to bring us to our deathbeds?
Worldwide, scientists have been working tirelessly to prepare for
when our main line of defense finds itself compromised. While
studying antibiotic-producing bacteria known as actinomycetes,
researchers in the Wright lab at McMaster University in
Canada stumbled upon possible solutions: two new functional
antibiotics, and a way to predict more.
All this was a result of mapping ancestry. Rather than directly
searching for a new antibiotic, Wright’s research team sought to
investigate more broad-ended ideas. The motivating factor was a
simple question: “What are the origins of antibacterial resistance?”
Wright said. Many antibiotics, including penicillin, are derived from
biological organisms. Wright and his team first sought out ancestral
history of the antibiotic properties of actinomycetes, bacteria
found in soil that manufacture many of our current antibiotics.
Actinomycetes derive their antibiotic-producing capabilities from
biosynthetic gene clusters (BGCs)—groups of two or more genes
that, coupled together, encode a pathway for the production of a
specific metabolite, such as a product with the antibiotic properties
we need. The researchers first gathered sequences of antibiotic
BGCs from multiple actinomycete species. Then, they began slowly
building phylogenetic trees—diagrams mapping out evolutionary
relationships—of the BGCs, looking for a common ancestor. As
this effort advanced, they noticed previously untapped antibiotic
BGCs. This gave rise to another fundamental question: “Where do
these things come from?” Wright asked.
As the researchers continued to investigate, they found that some
of these newly discovered gene clusters encoded products that
blocked bacteria in entirely different ways than existing antibiotics.
These genes could then be purified and expressed—taken from the
bacteria in question and “shown [without other genes] in the way,”
www.yalescientific.org
Wright said—to create new antibiotics. The researchers had found
a way to predict possible antibiotics derived from actinomycetes.
Due to this mapping, they were able to specifically find two new
functioning glycopeptide antibiotics: complestatin and corbomycin.
Glycopeptide antibiotics combat bacteria by binding to peptidoglycan,
an important substance that makes up cell wall. Complestatin and
corbomycin have a novel mode of action. Unlike other antibiotics,
which prevent the bacterial cell wall from being built, complestatin
and corbomycin keep it from being broken down, a critical step
during bacterial reproduction. As a result, the targeted bacteria cannot
divide and increase their numbers, and their harmful properties are
blocked. In mouse models, complestatin and corbomycin diminished
infection while maintaining a low rate of resistance development, a
promising sign in this early stage of research.
Wright’s team faced several challenges on the way. For one, the mere
act of constructing phylogenetic trees presented difficulties, as they had
to comb through many genetic sequences to find the links proving their
evolutionary relationships. Similarly, challenges also arose in purifying
and expressing these genes once they were identified. The researchers
faced a game of trial and error, changing a range of conditions to
investigate their effects on the production of functional antibiotics by
the bacteria. It was “like fishing in a pond,” Wright said; in this case,
they were looking for a rather small fish in a very large pond.
Where will this new discovery head? “Our plan is to continue to
look for new antibiotics of this new family,” Wright said, noting that
his lab has already identified several potential leads. He also hopes to
extend the methods used in this paper to investigate another antibiotic
family. “We have not yet decided on which one, but we are very hopeful
that the method will uncover new compounds,” Wright said.
Antibiotic resistance, especially today, is a larger problem than
you might envision. A world where antibiotics no longer work is
a world where a small cut could have a prognosis as foreboding as
cancer. We have to start looking at more creative ways to solve this
growing crisis. Wright’s team has begun thinking outside the box
already, which begs the question: what can we expect next? ■
Culp, E.J., Waglechner, N., Wang, W. et al. (2020). Evolutionguided
discovery of antibiotics that inhibit peptidoglycan
remodelling. Nature 578, 582–587. https://doi.org/10.1038/
s41586-020-1990-9
September 2020 Yale Scientific Magazine 29