University of Oregon researchers have developed a promising combination drug therapy that demonstrates unprecedented efficacy against bacterial infections in chronic wounds, potentially offering new hope for patients facing difficult-to-treat conditions like diabetic foot ulcers.
The research, published September 29 in Applied and Environmental Microbiology, reveals that adding small doses of chlorate to standard antibiotics creates a synergistic effect that is 10,000 times more effective at killing Pseudomonas aeruginosa bacterial cells in laboratory conditions compared to single-drug antibiotic treatments.
Breakthrough in Antibiotic Potency
The combination therapy pairs chlorate, a simple molecule harmless to mammals and humans at low doses, with conventional antibiotics to dramatically enhance their effectiveness. According to Melanie Spero, assistant professor of biology in the University of Oregon's College of Arts and Sciences and senior author of the study, this potency allows for significant dose reduction.
"With a small amount of chlorate in the mix, her team could use 1 percent of the standard dose of the broad-spectrum antibiotic ceftazidime," the research found. This 99% dose reduction could have profound implications for patient care, potentially shortening antibiotic treatment duration and reducing associated toxicity risks.
The research was funded by a $1.84 million grant over five years from the National Institutes of Health, building on Spero's previous work conducted as a postdoctoral scholar at the California Institute of Technology.
Addressing Critical Medical Need
Chronic wounds represent a significant healthcare challenge, particularly diabetic foot ulcers, which affect approximately 1 in 4 people with Type 2 diabetes according to American Diabetes Association research. More than half of these cases become infected, and when severe, 1 in 5 diabetic foot ulcers require amputation.
"An active infection is the most common complication that prevents the wound from healing and closing," Spero explained. "It's very debilitating, but there's not a lot of microbiology research being done in this field. So it's an opportunity to make a big difference."
Targeting Oxygen-Limited Environments
The innovation addresses a fundamental challenge in treating chronic wound infections: the low-oxygen conditions that promote antibiotic resistance. In oxygen-limited wound sites, bacteria switch to nitrate respiration for energy, slowing their growth but allowing survival and continued spread.
This metabolic shift makes P. aeruginosa particularly tolerant to conventional antibiotics, which are typically tested and rated based on their effectiveness against fast-growing bacteria in oxygen-rich conditions. The chlorate-antibiotic combination specifically targets this vulnerability.
"When the antibiotics are combined with a small molecule called chlorate, it stresses the bacterial cell in a way that makes it super susceptible to antibiotics," Spero said.
Clinical Implications and Future Directions
The potential clinical benefits extend beyond wound care. "In the case of chronic infections, people are often on antibiotics for long periods of time, and that can wreak havoc on the body," Spero noted. "Drugs with high toxicities can disrupt gut microbes and have severe side effects. Anything we can do to shorten the amount of time that a person is going to be on antibiotics and lower the dosage, the better."
However, clinical translation remains distant. The results come from controlled laboratory tests on bacterial cell cultures, and chronic infections typically involve complex microbial communities rather than single bacterial species. Understanding how drug combinations affect these complex communities in model organisms represents the next research phase.
Mechanism and Broader Applications
The exact mechanism by which chlorate enhances antibiotic effectiveness remains under investigation. Scientists know that chlorate hijacks nitrate respiration, completely eliminating microbes in oxygen-free environments. However, in varying oxygen conditions, bacteria can repair damage and tolerate the chemical, which has led to chlorate being overlooked in traditional high-oxygen drug screenings.
"I think that drug combinations will be a critical approach that helps us fight against the rise of antibiotic resistance," Spero said. "Finding examples of synergy among antimicrobials that are already on the market is going to be really valuable. And we'll need to dig further into the mechanisms behind why they work well together."
The research team's goal is to understand the biological machinery that makes bacteria susceptible to various antibiotics during chlorate exposure. This mechanistic understanding could enable rational drug design using already-approved molecules, moving beyond the current "guessing game" approach to testing drug combinations.
"This will have important implications not only for treating chronic wound infections but also broadly for the infectious disease field and our fight against antibiotic resistance and treatment failure," Spero concluded.
