It's a familiar scenario in medicine: A patient takes the antibiotic their doctor prescribes, and it just doesn't work.
"If you have an infection and you take amoxicillin, drink the pink liquid, but the infection doesn't go away, that means the bacteria are no longer able to be killed by that drug. They've become resistant, and you have to keep hitting them with new antibiotics to kill them," said Amanda Wolfe, who chairs UNC Asheville's chemistry department, "
It's happening more often, in more hospitals, as bacteria evolve faster than the drugs meant to stop them. Wolfe and her research partner, UNCA biochemistry professor Ryan Steed, have spent years trying to get ahead of that curve. This spring, for the second time, they won a $500,000 grant from the National Institutes of Health to keep trying.
Skipping the targets bacteria already know how to beat
Most antibiotics work by hitting one specific weak point in a bacterial cell. The trouble, Wolfe says, is that resistance rarely stays contained. When bacteria adapt to survive one antibiotic, they often gain resistance to an entire family of related drugs at once.
So instead of engineering another drug aimed at that same kind of weak point, Wolfe and Steed are going after something bacteria can't route around as easily: the way they generate power, an area that's Steed's specialty.
"My focus is on how cells produce energy," Steed said. "Human cells do this, bacterial cells do this, and we're trying to look at the specific ways that bacteria do it so that we can find weaknesses that we can exploit."
That ability to generate energy, Wolfe and Steed said, is something bacteria can't survive without, which makes it a far harder target to evolve around than the ones older antibiotics rely on.
The two bacteria at the center of this project, Pseudomonas aeruginosa and Acinetobacter baumannii, aren't obscure threats. Both are officially designated as critical priority pathogens by the World Health Organization, meaning they're among the drug-resistant bacteria the agency considers most urgent to develop new treatments for, and both are common causes of infections acquired in hospitals.
A grant built differently
At most research universities, this kind of drug-discovery work belongs to graduate students and postdocs. UNC Asheville doesn't have any. So instead, every experiment runs through undergraduates, mentored directly by Wolfe and Steed but driving the science themselves.
"It really puts them in a tier above other undergraduates who are applying for jobs, applying for graduate programs," Wolfe said, "because they present at national conferences alongside graduate students and faculty, and they get their names on published papers."
The grant, an NIH award built specifically for colleges without graduate programs, funds paid research positions. Wolfe said that matters most for students who couldn't otherwise afford to do research at all. "An unpaid internship is just not accessible to them," she said. "Being able to provide a paid position, where they're working up to 40 hours a week for 10 weeks in the summer, makes it so that they can really focus on this without having to work a couple hours and then go work an eight-hour shift. It really makes it so that it's a much more level playing field."
What comes next
This summer, that work is happening in UNC Asheville's own labs. Eventually, some of it will travel further through a research partner also funded by this grant at the University of Massachusetts Amherst. Dr. Vince Rotello's lab tests early-stage antibiotic candidates in a living infection model, a step closer to how the drug might actually be used, though still a long way from an approved treatment.
Wolfe and Steed are matter-of-fact about how far off any real medicine still is. Their first grant ran out before this one began, and the research didn't stop. It just moved more slowly. That's what the work looks like, they said: Not a race with a finish line, but researchers adapting to stay a step ahead of bacteria doing the same thing.
