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A new antibacterial treatment approach to combat life-threatening infections in patients with cystic fibrosis

Published on March 4, 2024

Cystic fibrosis, a rare genetic disease, affects 7,743 people in^France,¹ or one in every 4,000 to 5,000 births. This condition, characterized by the production of thick, viscous mucus, primarily affects the lungs and the digestive system. Recurrent respiratory infections are the leading cause of death among patients, whose life expectancy averages between 40 and 50 years. The opportunistic bacterium Pseudomonas aeruginosa is responsible for the majority of infection-related deaths. Repeated use of antibiotics to eliminate it leads to the emergence of resistant strains, which are often fatal for these patients. A research team in Strasbourg, working at the intersection of chemistry and biology, is developing a brand-new antibiotic that targets, among other bacteria, Pseudomonas aeruginosa. Myriam Seemann, a research director at the CNRS and head of the Laboratory of Biological Chemistry and Therapeutic Applications (CBAT) at the Strasbourg Institute of Chemistry, reflects on the origins of this innovative project: “A few years ago, we discovered two new enzymes essential for the survival of certain bacteria, particularly those found in patients with cystic fibrosis. Since human cells do not use these enzymes, they are prime targets for blocking bacterial proliferation and preventing the deaths of many patients. These highly specific enzymes have been little studied because they are very unstable (they degrade upon contact with oxygen). “Our laboratory has developed unique expertise in purifying and characterizing these enzymes to better understand their mechanisms of action, with the goal of leveraging this knowledge to develop new antibiotics.”

This discovery, which earned Dr. Seemann the CNRS Bronze Medal, is now being pursued by a young researcher at the lab who began her doctoral thesis in 2020 thanks to European funding. “During my thesis, I participated in the study of a molecule that inhibits one of these bacterial enzymes, called IspH. In vitro, the activity of IspH in the bacterium Pseudomonas aeruginosa is completely blocked by this molecule—which is very encouraging! However, a major challenge remains: finding a way to get this IspH inhibitor inside the bacteria, ” explains Gabriella Ines Bianchino, the Italian doctoral student leading the project. “Thanks to the support of the organizations Vaincre la Mucoviscidose and Grégory Le Marchal, I have an additional six months to modify a small part of the inhibitory molecule so that it can cross the bacterial cell wall and neutralize its target enzyme.”

If this crucial step is successfully completed, the resulting molecule will be the very first in a new class of antibiotics—a revolution in this field, where the last class of antibiotics to be discovered and subsequently used successfully dates back to … the late 1980s! The next step will be to evaluate the toxicity of this molecule on human cells, then to conduct tests on animal models before beginning clinical trials.

Ultimately, the goal is to provide an additional treatment option for patients with cystic fibrosis and, more broadly, a new therapeutic tool in the fight against antibiotic resistance—a scourge classified by the WHO as one of the 10 greatest threats to^global public health.²

Gabriella Ines Bianchino, a doctoral student at the CBAT Laboratory, uses a glove box where an inert, oxygen-free atmosphere is essential for studying highly unstable bacterial enzymes.