The ability to treat infections is essential in medicine. Without it, the risks of transplants or surgeries multiply, as do the risks for patients receiving chemotherapy for cancer who are vulnerable to fatal infections. Since the discovery of antibiotics, pathogens have adapted to the man-made enemy and super-resistant bacteria already pose a global health threat, causing more than a million deaths each year.
Resistance occurs more often in so-called gram-negative bacteria, which have two membranes that are difficult for many antibiotics to pass through. One of them, Acinetobacter baumannii, represents one of the major threats in hospitals and was very common during the Covid epidemic. The World Health Organization has identified it as an urgent threat that requires new antibiotics. It has been more than 50 years since the FDA, the drug regulator in the United States, approved a new drug against a gram-negative bacterium.
Today the journal Nature publishes a work signed by scientists from the pharmaceutical company Roche that explains how zosurabalpine, a novel antibiotic capable of overcoming the resistance of A. baumannii, was discovered and developed. The team, led by Michael Lobritz and Kenneth Bradley, searched a database of around 45,000 synthetic peptides, molecules that are not the basis of most antibiotics and come from nature. Among them, he identified several molecules with antibacterial activity, selected one of them and then optimized it to improve its effectiveness and safety. The drug, which has already cured mice with pneumonia caused by A. baumannii, is being used for the first time in humans in a Phase I trial to test its safety.
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Zosurabalpine uses a different mechanism to overcome the defenses that normally make these bacteria resistant. It blocks the transport of a molecule, lipopolysaccharide, to the surface of the bacteria, where it is necessary to form the outer membrane of these microorganisms. This is achieved by crossing only one of the two membranes of gram-negative bacteria. Without this outer membrane, A. baumannii has a lower chance of survival and becomes susceptible to other antibiotics that could be combined with zosurabalpine to treat these types of infections.
“Peptides have been studied as antimicrobials for many years, colistin itself is a peptide, but the site in which this new antibiotic acts in the transport of lipopolysaccharides is new,” explains Rafael Cantón, head of the microbiology service at the Ramón y Cajal University Hospital in Madrid . “It is interesting that it can be used against Acinetobacter as there are few therapeutic options. That’s the good thing about it, but it won’t be a panacea,” he says. “There is something that worries me because they see that there is a probability that they will develop non-negligible resistant mutants,” concludes the spokesman for the Spanish Society of Infectious Diseases and Clinical Microbiology (SEIMC).
Bruno González Zorn, director of the Department of Antimicrobial Resistance at the Complutense University of Madrid, believes that this new antibiotic “can contribute a lot because A. baumannii infections are important and increasing.” In Spain, about 50% of the Samples analyzed were resistant to the usual treatments, so “new tools are needed,” adds González Zorn. The researcher points out that he is working with peptides, which Roche scientists have been pursuing for a long time, and that bacteria use them to fight against each other. They are also a weapon of phages, viruses that attack these microbes, and are also used against antibiotic-resistant infections. However, in the work published today in Nature, problems of toxicity or distribution have been overcome, making zosurabalpine a promising molecule.
In the fight against antibiotic resistance, the obstacles are not only scientific. “Apart from how quickly bacteria evolve, the problem is that the antibiotic market has almost disappeared, because after the cost of starting a series of research and developing clinical trials, if we can do it, that's the end “To achieve this and have a new antibiotic, it is very difficult to make it profitable,” says Daniel López, an expert in superbugs at the National Center for Biotechnology of the CSIC. Due to the nature of antibiotics, which must be used very carefully to kill bacteria without being able to adapt to them, new drugs have to be saved while the old ones, which have been off patent for decades, still work. This peculiarity has led institutions such as the European Union to consider public incentives such as the expansion of other medicines to companies developing new antibiotics in order to make their development interesting.
A second study, also published today by Nature, adds information about how the lipopolysaccharide transport system to the cell surface works to form the outer membrane and how the new antibiotic blocks it. This knowledge is being used to search for new compounds aimed at disabling this mechanism and creating tools against bacterial resistance, a problem that some estimates suggest could be the leading cause of death worldwide by 2050.
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