The ability to treat infections is essential in medicine. Without it, the risks of transplants or surgeries are multiplied, as are those of patients receiving chemotherapy for cancer, vulnerable to lethal infections. Since the discovery of antibiotics, pathogens have been adapting to the enemy created by humans and super-resistant bacteria are already a global health threat. They cause more than a million deaths a year.
Resistance is more common among so-called grammnegative bacteria, which have two membranes that are difficult for many antibiotics to pass through. One of them, the Acinetobacter baumannii, is one of the great threats in hospitals and was very frequent during the covid epidemic. The World Health Organization has identified it as an urgent threat for which new antibiotics are required. It has been more than 50 years since the FDA, the body that regulates medicines in the United States, has approved a new drug against a gram-negative bacteria.
Today, the magazine Nature publish a jobsigned by scientists from the pharmaceutical company Roche, which explains how zosurabalpine was discovered and developed, a new type of antibiotic that can overcome the resistance of the A. baumannii. The team, led by Michael Lobritz and Kenneth Bradley, searched a database of some 45,000 synthetic peptides, molecules other than those that are usually the basis of most antibiotics, obtained from nature. Among them, he identified several molecules with antibacterial activity, among which he selected one, which he then optimized to improve its effectiveness and safety. The drug, which has already cured mice with pneumonia caused by A. baumanniihas begun to be used in humans, in a phase I trial, to test its safety.
Zosurabalpine overcomes the defenses that usually make this bacteria resistant with a different mechanism. It blocks the transport of a molecule, lipopolysaccharide, to the surface of the bacteria, where it is necessary to create the outer membrane of these microorganisms. It achieves this by overcoming only one of the two membranes that Gram-negative bacteria have. Without that outer membrane, the A. baumannii It is less likely to survive and becomes vulnerable to other antibiotics, which could be combined with zosurabalpine to treat these types of infections.
“Peptides have been studied as antimicrobials for many years, the same colistin It is a peptide, but the place where 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 because there are few therapeutic options. That is the good part, but it is not going to be a panacea,” he says. “There is something that leaves me worried, because they see that there is a probability that they will develop non-negligible resistant mutants,” concludes the spokesperson for the Spanish Society of Infectious Diseases and Clinical Microbiology (SEIMC).
Bruno González Zorn, director of the Antimicrobial Resistance Unit at the Complutense University of Madrid, considers that this new antibiotic “can contribute a lot because A. baumannii “They are important and they are increasing.” In Spain, approximately 50% of the samples analyzed are resistant to the usual treatments, so “new tools are necessary,” adds González Zorn. The researcher points out that he has been working with peptides like those that Roche scientists have tracked 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 infections resistant to antibiotics. However, in the work that he publishes today Nature Toxicity or distribution problems have been overcome that make zosurabalpine a promising molecule.
In the fight against antibiotic resistance, the obstacles are not only scientific. “In addition to how quickly bacteria evolve, the problem is that the antibiotic market has almost disappeared, because after what it costs to launch a line of research and develop clinical trials, if we manage to reach the end and have a new antibiotic, it is very difficult to make profitable,” says Daniel López, an expert in superbacteria at the National Center for Biotechnology of the CSIC. Due to the very nature of antibiotics, which must be used very carefully to kill bacteria without allowing them to adapt to them, new drugs must be saved while the old ones, which have been off patent for decades, still work. This particularity has made institutions such as the European Union consider public incentives, such as the extension of other drugs to companies that develop new antibiotics, to make their development interesting.
In a second studywhich also publishes today Nature, information is added about the way in which the lipopolysaccharide transport system works to the surface of the cell to generate the outer membrane and how the new antibiotic blocks it. This knowledge will be used to search for new compounds aimed at deactivating this mechanism and creating tools against bacterial resistance, a problem that, according to some estimatesmay be the leading cause of global death in 2050.
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