University of Fribourg researchers have managed to demonstrate both the effectiveness and the limits of a new molecule (xeruborbactam) in treating certain antibiotic-resistant bacteria. According to WHO, microbial resistance is one of the 10 greatest threats to public health now facing humanity. The study has appeared in one of the prestigious journals published by the American Society for Microbiology.

Antibiotic resistance is a genuine scourge that is undermining the successes modern medicine has achieved. Without effective antibiotics, a certain number of potentially serious infections could not be treated and the positive outcomes of many surgical operations and organ transplants would be totally compromised. It would spell a return to the world before the invention of penicillin. Dr. Laurent Poirel is a Senior Researcher at the University of Fribourg and the Director of NARA, the National Reference Center for Emerging Antibiotic Resistances and Resistance Mechanisms. As Dr. Poirel explains, “The problem is rooted in the inappropriate use of antibiotics. If antibiotics are prescribed recklessly, for instance in treating a simple cold, or if a treatment is stopped too early, we are giving bacteria a chance not only to survive but to become more resistant to antibiotics. These newer bacteria are going to multiply and pass along their resistance to their descendants.”

Scientists are therefore racing against time with respect to a phenomenon that could become a public health disaster. In this context, the team at the University of Fribourg’s Medical and Microbiological Unit has analyzed the strengths and weaknesses of the molecule xeruborbactam. A new treatment is about to enter the clinical stage.

Enzyme inhibitors
To defend themselves against the bactericidal action of certain antibiotics, bacteria in some cases produce enzymes called metallo-β-lactamases. Dr. Christopher Le Terrier, one of the main authors of the study, pointed out that “these constitute an impenetrable line of defense for most current antibiotics, rendering them ineffective.” To remedy the problem, the pharmaceutical industry has recently chalked up a success by developing the new molecule xeruborbactam, an inhibitor that blocks the action of these enzymes. By combining an antibiotic and this new enzyme inhibitor, the medical researchers were able to recover the antibacterial action of the antibiotic.

The UniFri researchers then sought to evaluate the activity of this inhibitor against the most resistant bacteria circulating in Switzerland and elsewhere in the world. They targeted in particular bacteria producing enzymes that are the most “destructive” to antibiotics used against two common types of bacteria, Escherichia coli (responsible for urinary infections) and Pseudomonas aeruginosa (which can cause pulmonary and intra-abdominal infections).

Positive results... but there’s a catch
Dr. Poirel, pleased by the preliminary results, eagerly spoke of the bright side first, “By combining xeruborbactam with antibiotics like ceftazidime or cefepime, we noticed that the E. coli bacteria became much more sensitive to the antibiotics, which is very good news.”

On the other hand, the researchers saw that the new drug was much less effective against P. aeruginosa. “The latter is able to activate a defense mechanism, a kind of pump that ejects the antibiotics but also the new inhibitor before they can reach their targets,” Dr. Poirel explained.

Even more concerning, the scientists noted an altogether unexpected result, that some P. aeruginosa bacteria producing extremely specific enzymes could also be resistant to the inhibitory action of xeruborbactam, rendering use of the new treatment ineffective. “It’s worrying because we know this enzyme, which is found in several types of bacteria, is the cause of resistance to many antibiotics in countries like Japan, South Korea, China, and Brazil,” Dr. Le Terrier stressed.

Faced with this problem, the Microbiology Unit of the University of Fribourg has a leading role to play. By identifying the escape routes and mechanisms of multi-resistant bacteria, the Microbiology Unit is making the work of the pharmaceutical industries easier. Dr. Poirel summed up the importance of the team’s research, “In a nutshell, we are pointing out the path to go down or not to go down in future research aimed at developing new molecules.”

The fight goes on
Published in the journal Antimicrobial Agents and Chemotherapy of the American Society for Microbiology, the researchers’ paper makes clear that xeruborbactam has proven reasonably effective against a large number of bacteria that have a range of resistance mechanisms. But the paper also undercuts the conclusions of earlier studies that were more optimistic. “Xeruborbactam is not a panacea! So we aren’t at the end of the road yet, and the endless search for new and even more effective molecules remains crucial,” Dr. Poirel concluded.

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Since 2018, NARA, based at the University of Fribourg, has been the prime national center for the early detection of emerging strains that are resistant to antibiotics. The center’s aim is to limit the spread of such strains and issue recommendations to the Federal Office of Public Health.

Le Terrier C., Freire S., Viguier C., Findlay J., Nordmann P., Poirel L. (2024). Relative inhibitory activities of the broad-spectrum β-lactamase inhibitor xeruborbactam in comparison with taniborbactam against metallo-β-lactamases produced in Escherichia coli and Pseudomonas aeruginosa. Antimicrobial Agents and Chemotherapy, 68(6), e01570-23. https://doi.org/10.1128/aac.01570-23