Buffalo: Like a dairy farmer tending to a herd of
cows to produce milk, researchers are tending to colonies of the
bacteria Escherichia coli (E. coli) to produce new
forms of antibiotics — including three that show promise in
fighting drug-resistant bacteria. The research, published today (May 29) in the journal Science
Advances, was led by Blaine A. Pfeifer, an associate professor of
chemical and biological engineering in the University at Buffalo
School of Engineering and Applied Sciences. For more than a decade, Pfeifer has been studying how to
engineer E. coli to generate new varieties of erythromycin,
a popular antibiotic. In the new study, he and colleagues report
that they have done this successfully, harnessing E. coli to
synthesize dozens of new forms of the drug that have a slightly
different structure from existing versions.
Three of these new varieties of erythromycin successfully killed
bacteria of the species Bacillus subtilis that were
resistant to the original form of erythromycin used clinically.
“We’re focused on trying to come up with new
antibiotics that can overcome antibiotic resistance, and we see
this as an important step forward,” said Pfeifer, PhD.
“We have not only created new analogs of erythromycin, but
also developed a platform for using E. coli to produce the
drug,” he said. “This opens the door for additional
engineering possibilities in the future; it could lead to even more
new forms of the drug.”
The study is especially important with antibiotic resistance on
the rise. Erythromycin is used to treat a variety of illnesses,
from pneumonia and whooping cough to skin and urinary tract
infections.
E. coli as a factory
Getting E. coli to produce new antibiotics has been
something of a holy grail for researchers in the field.
That’s because E. coli grows rapidly, which speeds
experimental steps and aids efforts to develop and scale up
production of drugs. The species also accepts new genes relatively
easily, making it a prime candidate for engineering.
While news reports often focus on the dangers of E. coli,
most types of this bacteria are actually harmless, including those
used by Pfeifer’s team in the lab.
Over the past 11 years, Pfeifer’s research has focused on
manipulating E. coli so that the organism produces all of
the materials necessary for creating erythromycin. You can think of
this like stocking a factory with all the necessary parts and
equipment for building a car or a plane.
With that phase of the research complete, Pfeifer has turned to
the next goal: Tweaking the way his engineered E. coli
produce erythromycin so that the drug they make is slightly
different than versions used in hospitals today.
That’s the topic of the new Science Advances paper.
The process of creating erythromycin begins with three basic
building blocks called metabolic precursors — chemical
compounds that are combined and manipulated through an assembly
line-like process to form the final product, erythromycin.
To build new varieties of erythromycin with a slightly different
shape, scientists can theoretically target any part of this
assembly line, using various techniques to affix parts with
structures that deviate slightly from the originals. (On an
assembly line for cars, this would be akin to screwing on a door
handle with a slightly different shape.)
In the new study, Pfeifer’s team focused on a step in the
building process that had previously received little attention from
researchers, a step near the end.
The researchers focused on using enzymes to attach 16 different
shapes of sugar molecules to a molecule called 6-deoxyerythronolide
B. Every one of these sugar molecules was successfully adhered,
leading, at the end of the assembly line, to more than 40 new
analogs of erythromycin — three of which showed an ability to
fight erythromycin-resistant bacteria in lab experiments.
“The system we’ve created is surprisingly flexible,
and that’s one of the great things about it,” Pfeifer
said. “We have established a platform for using E.
coli to produce erythromycin, and now that we’ve got it,
we can start altering it in new ways.”
- See more at: http://www.buffalo.edu/news/releases/2015/05/049.html#sthash.TA4YRcoK.dpuf