Researchers have successfully harnessed the bacteria Escherichia coli to generate dozens of new forms of the commonly used antibiotic erythromycin.
Three of these new varieties were able to kill bacteria of the species Bacillus subtilis, which are 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,” says Blaine A. Pfeifer, associate professor of chemical and biological engineering at University at Buffalo.
“We have not only created new analogs of erythromycin, but also developed a platform for using E. coli to produce the drug. This opens the door for additional engineering possibilities in the future; it could lead to even more new forms of the drug.”
Published in the journal Science Advances, the study is especially important with antibiotic resistance on the rise, Pfeifer says. Erythromycin is used to treat a variety of illnesses, from pneumonia and whooping cough to skin and urinary tract infections.
Getting E. coli to produce new antibiotics has been something of a holy grail for researchers in the field.
That’s because it 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 these bacteria are actually harmless, including those used in the current study.
Pfeifer’s research has focused on manipulating E. coli so that the organism produces all of the materials necessary for creating erythromycin—think of it like stocking a factory with all the necessary parts and equipment for building a car or a plane.
3 building blocks
With that phase of the research complete, researchers have turned to the next goal: tweaking the way the engineered E. coli produce erythromycin so that the synthesized drug is slightly different than versions used in hospitals today.
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, the researchers focused on a step in the building process that had previously received little attention—a step near the end.
They 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 says. “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.”
Source: University at Buffalo