FDA-approved chronic kidney disease drug may help mitigate antibiotic resistance

FDA-approved chronic kidney disease drug may help mitigate antibiotic resistance

Increased use of antibiotics may, seemingly paradoxically, lead to more problematic infections as bacteria evolve to resist treatment. The answer to this antimicrobial resistance, which the Centers for Disease Control and Prevention has called "one of the world's most pressing public health problems," could be a drug for kidney disease, according to a team led by Penn State researchers.

Antibiotics kill or stop the growth of bacteria, but the more they are used, the better bacteria resist them. The team found that the US Food and Drug Administration (FDA)-approved drug sevelamer, typically prescribed to bind excess phosphorus in the blood of people with chronic kidney disease undergoing dialysis, also binds off-target antibiotics in mice. Antibiotics are said to be “off-target” when they appear in the body outside the site of infection – in this case a small portion escapes the bloodstream and is excreted into the intestines.

The researchers published their findings, which they said in the journal Small, provide a way to mitigate antibiotic resistance. The idea is that the sevelamer will find and bind the off-target antibiotics and stop them from interacting with bacteria in the gut, like a dog would to prevent 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 the evolution of resistance without compromising systemic antibiotic efficacy. “

Amir Sheikhi, corresponding author, Dorothy Foehr Huck and J. Lloyd Huck, chair of Biomaterials and Regenerative Engineering and assistant professor of chemical engineering

Vancomycin is often prescribed to treat infections caused by enterococci, which exist in the intestines but can grow in numbers 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 are turning to daptomycin as a last-line treatment to combat the infection. According to Sheikhi, these types of infections are particularly prevalent in healthcare settings, where patients have already undergone lengthy antibiotic treatments for primary infections or are developing primary infections following a medical procedure.

The problem is that the bacteria can also evolve to resist daptomycin. The resistance comes about, Sheikhi said, because 5% to 10% of antibiotics administered intravenously end up in the gastrointestinal tract. There the off-target antibiotics do not match the number of bacteria that survive the drug and evolve to avoid being affected by the drugs to kill them. To combat this, researchers are developing ways to capture the off-target antibiotics and prevent the bacteria from evolving in a way that renders the drugs ineffective.

"Developing anti-antibiotics instead of new antibiotics can potentially protect the effectiveness of current antibiotics," said Sheikhi, who is also affiliated with the Penn State Districs of Biomedical Engineering, Chemistry and Neurosurgery and directs the University's Bio-Soft Materials Laboratory, or B-Smal.

He explained that as bacteria continue to develop resistance to antibiotics, researchers can explore alternative therapies that may go beyond stronger antibiotics. One such way forward is to administer a drug that can capture off-target antibiotics along 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 former Eberly Professor of Biotechnology and co-author in the current study — that found cholestyramine, an FDA-approved treatment for high-profile cholesterol, that daptomkin had inactivated Daptomycin was able to inactivate.

“Antibiotics lead to 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 antibiotics from ever emerging in the gut."

In 2022, Sheikhi, Read and other collaborators described the mechanism -cholestyramine was used to bind daptomycin, but also that it could not remove vancomycin. So the team turned to another promising candidate: Sevelamer.

In this study, researchers injected mice with Enterococcus faecium with vancomycin or saline, a type of intestinal bacteria known to rapidly develop antibiotic resistance. At the same time, they fed the oral suspension of sevelamer to the mice. The researchers then analyzed the genetic content of the feces from the mice.

"Our results show that sevelamer captures low concentrations of daptomycin within minutes and within a few hours," said Sheikhi, noting that sevelamer removed both antibiotics - blocking the antibiotic activity of daptomycin in vitro, which means cell experiments, and vancomycin in vivo and in vivo and in vivo, e.g. B. in VIVO, e.g. B. in an animal model. “This introduces sevelamer as a more versatile and effective adjunctive therapy to reduce the development of resistance in infections that may originate from healthcare settings.”

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

“To our knowledge, this is the first demonstration that an FDA-approved drug can effectively block the emergence of vancomycin-driven resistance in living organisms and represents a novel and scalable strategy to combat antimicrobial resistance in healthcare,” Sheikhi said. “Because sevelamer is already approved by the FDA, it has a well-established safety profile, making it a strong candidate for clinical use.”

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 study whether sevelamer could prevent the development of resistance to other types of antibiotics that are secreted in the gastrointestinal tract. The research team invites staff with experience in clinical trials assessing antimicrobial resistance to contact them.

Other authors on the paper affiliated with Penn State include Roya Koshani, a postdoctoral researcher in chemical engineering; Shang-Lin Yeh, who received his doctorate in chemical engineering from Penn State and now works in industry. Zeming HE, who earned a bachelor's degree in chemical engineering from Penn State and is now pursuing a graduate degree at the University of Pennsylvania; and Naveen Narasimhalu, who earned a bachelor's degree in chemical engineering from Penn State and now works at 3M; Landon G. Vom Steeg, postdoctoral researcher in biology and entomology; and Derek G. Sim, associate research professor of biology and 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 Biological 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 initiative of Patricia and Stephen Benkovic; the Dorothy Foehr Huck and J. Lloyd Huck Early Career Chair; the College of Agriculture Applied Evolution Seed Grant Program; and the Eberly chairman of biotechnology supported this research.

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