FDA-approved dialysis drug may help fight against antimicrobial resistance

UNIVERSITY PARK, Pa. — Increased antibiotic use can lead, seemingly paradoxically, to more problematic infections, as the bacteria evolve to resist the treatment. The answer to this antimicrobial resistance, which the Centers for Disease Control and Prevention called “one of the world’s most urgent public health problems,” might be a medication used for kidney disease, according to a team led by researchers at Penn State.

Antibiotics kill or stop the growth of bacteria, but the more they are used, the better bacteria become at resisting them. The team found that the U.S. Food and Drug Administration (FDA)-approved drug sevelamer, typically prescribed to help bind excess phosphorus in the blood of people with chronic kidney disease undergoing dialysis, could also bind off-target antibiotics in mice. Antibiotics are labeled as “off-target” when they appear in the body away from the infection site — in this case, a small portion escapes the bloodstream and is excreted into the gut.

The researchers published their results, which they said suggest a way to help mitigate antibiotic resistance, in the journal Small. The idea is that the sevelamer can find and bind the off-target antibiotics, preventing them from interacting with bacteria in the gut, like leashing a dog to keep it from chasing a squirrel.

“We found that sevelamer can act as an ‘anti-antibiotic’ by capturing off-target vancomycin and daptomycin — two commonly prescribed antibiotics — in the gut, preventing resistance evolution without compromising systemic antibiotic effectiveness,” said corresponding author Amir Sheikhi, the Dorothy Foehr Huck and J. Lloyd Huck Early Career Chair in Biomaterials and Regenerative Engineering and assistant professor of chemical engineering.

Vancomycin is often prescribed to treat infections caused by enterococci, which exist in the gut but can grow in number and spread to other areas of the body, leading to urinary tract infections, infections in the heart, cellulitis and more. However, the bacteria can evolve to resist vancomycin, so clinicians turn to daptomycin as a last-line treatment to fight the infection. According to Sheikhi, these types of infections are especially prevalent in health care settings, where patients have already undergone lengthy antibiotic treatments for primary infections or develop primary infections after a medical procedure.

The problem is that the bacteria can evolve to resist daptomycin, too. The resistance comes about, Sheikhi said, because 5% to 10% of the antibiotics, administered intravenously, end up in the gastrointestinal tract. There, the off-target antibiotics are no match for the number of bacteria, which survive the medication and evolve to be unaffected by the drugs meant to kill them. To combat this, researchers are developing ways to capture the off-target antibiotics and prevent the bacteria from evolving in ways that render the medications ineffective.

“Developing anti-antibiotics, instead of new antibiotics, may be able to protect the effectiveness of current antibiotics,” said Sheikhi, who is also affiliated with the Penn State Departments of Biomedical Engineering, of Chemistry and of Neurosurgery and leads the Bio-Soft Materials Laboratory, or B-SMaL, at the University.

He explained that since bacteria can — and have — continued to develop resistance to antibiotics, researchers have turned to investigating alternative therapies beyond creating stronger antibiotics. One such path forward is administering a drug capable of capturing off-target antibiotics in tandem with the antibiotic.

The work builds on a 2020 study — led by Andrew Read, senior vice president for research, Evan Pugh Professor of Biology and Entomology, and formerly Eberly Professor of Biotechnology and co-author on the current study — that found cholestyramine, a drug approved by the FDA to treat high cholesterol, could inactivate daptomycin.

“Antibiotics drive antibiotic resistance,” Read said. “If you can inactivate antibiotics where they are not needed, you eliminate the driver of antibiotic resistance. An anti-antibiotic could in principle prevent resistance to antibiotic from ever emerging in the gut.”

In 2022, Sheikhi, Read and other collaborators described the mechanism cholestyramine used to bind daptomycin, but also found that it failed to remove vancomycin. So, the team turned to another promising candidate: sevelamer.

In this study, the researchers administered vancomycin or saline solution via injection to mice with Enterococcus faecium, a type of gut bacteria known to quickly evolve antibiotic resistance. At the same time, they fed the mice oral suspension of sevelamer. The researchers then analyzed the genetic content of fecal matter from the mice.

“Our findings show that sevelamer captures low concentrations of daptomycin within minutes and vancomycin within hours,” Sheikhi said, noting that sevelamer removed both antibiotics — blocking antibiotic activity of daptomycin in vitro, meaning cell experiments, and vancomycin in vitro and in vivo, meaning in an animal model. “This introduces sevelamer as a more versatile and effective adjunctive therapy for reducing resistance evolution in infections that can originate in health care settings.”

While the findings were made in mice, the researchers said there are direct implications for human medicine.

“To the best of our knowledge, this is the first demonstration that an FDA-approved drug can effectively block vancomycin-driven resistance emergence in live organisms, presenting a novel and scalable strategy to combat antimicrobial resistance in health care settings,” Sheikhi said. “Since sevelamer is already FDA-approved, it has a well-established safety profile, making it a strong candidate for clinical application.”

Next, Sheikhi said the team plans to conduct clinical trials to evaluate sevelamer’s effectiveness in human patients receiving vancomycin or daptomycin. They also plan to explore whether sevelamer might prevent resistance evolution of other types of antibiotics excreted into the gastrointestinal tract. The research team invites collaborators with experience in clinical trials for antimicrobial resistance evaluation to contact them.

Other authors on the paper affiliated with Penn State are Roya Koshani, postdoctoral scholar in chemical engineering; Shang-Lin Yeh, who earned his doctorate in chemical engineering at Penn State and now works in industry; Zeming He, who earned a bachelor degree in chemical engineering at Penn State and is now pursuing a graduate degree at the University of Pennsylvania; and Naveen Narasimhalu, who earned a bachelor degree in chemical engineering  at Penn State and now works at 3M; Landon G. vom Steeg, postdoctoral scholar in biology and in entomology; and Derek G. Sim, associate research professor of biology and of entomology. Robert J. Woods, associate professor of internal medicine — infectious diseases, University of Michigan, also co-authored the paper. Sheikhi, Sim and Read are also affiliated with the Huck Institutes of the Life Sciences at Penn State, and vom Steeg is also affiliated with the Geisel School of Medicine at Dartmouth.

Penn State’s Huck Institute of the Life Sciences through the Patricia and Stephen Benkovic Research Initiative; the Dorothy Foehr Huck and J. Lloyd Huck Early Career Chair; the College of Agriculture’s Applied Evolution Seed Grant Program; and the Eberly Chair of Biotechnology supported this research.