Zosurabalpine, a new type of antibiotic that successfully acts against deadly superbugs

The ability to treat infections is essential in medicine. Without it, the risks of transplants or surgeries are multiplied, and cancer patients receiving chemotherapy become vulnerable to lethal infections. Since the discovery of antibiotics, pathogens have been adapting to the enemy created by humans. Super-resistant bacteria are already a global health threat. They cause more than a million deaths each year.

Resistance is more common among so-called gram-negative bacteria, which have two membranes that are difficult for many antibiotics to pass through. One of them, Acinetobacter baumannii, is one of the great threats in hospitals. It was very common during the Covid-19 pandemic. 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 has approved a new drug against a gram-negative bacteria.

This Wednesday, the journal Nature published a work. Authored by scientists from the pharmaceutical company Roche, it explains how zosurabalpine — a new type of antibiotic that can overcome the resistance of A. baumannii — was discovered and developed. The research team, led by Michael Lobritz and Kenneth Bradley, searched a database of some 45,000 synthetic peptides, or molecules other than those that are usually the basis of most antibiotics obtained from nature. The researchers identified several molecules with antibacterial activity. They then selected one, which was subsequently optimized to improve its effectiveness and safety. The drug — which has already cured mice with pneumonia caused by A. baumannii — has 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, by applying a different mechanism. It blocks the molecule lipopolysaccharide from reaching the surface of the bacteria, where it’s necessary to create the outer membrane of these microorganisms. The antibiotic achieves this by overcoming only one of the two membranes that gram-negative bacteria have. Without that outer membrane, A. baumannii is less likely to survive and it 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. Colistin itself is a peptide, but the place where this new antibiotic acts — in the transport of lipopolysaccharides — is new,” explains Rafael Cantón, head of Microbiology at the Ramón y Cajal University Hospital in Madrid. “It’s interesting that it can be used against [A. baumannii], because there are few therapeutic options. That’s the good part, but it’s not going to be a panacea,” he emphasizes. “There’s something that worries me, because [the researchers] see that there’s the probability that [the bacteria] 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 — believes that this new antibiotic “can contribute a lot, because A. baumannii infections are important and are increasing.” In Spain, approximately 50% of the samples analyzed are resistant to the usual treatments, so “new tools are necessary,” González Zorn adds. The researcher points out that he’s been working with peptides — like those that the Roche scientists have tracked — for a long time. He explains that bacteria use them to fight against each other. They’re also a weapon utilized by bacteriophages — viruses that attack these microbes and are also used against infections resistant to antibiotics. However, in the work published by Nature, problems of toxicity or distribution have been overcome, making zosurabalpine a promising molecule.

In the fight against antibiotic resistance, the obstacles aren’t 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 new line of research and develop clinical trials — if we manage to reach the end and develop a new antibiotic — it’s very difficult to make a profit,” says Daniel López, an expert in superbugs at the Spanish National Center for Biotechnology.

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 take time to make, 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 offering the intellectual property rights of other drugs to companies that develop new antibiotics — to make their development feasible.

In a second study, also published by Nature on Wednesday, information is added about the way in which the lipopolysaccharide transport system works with regard to the surface of the cell, to generate the outer membrane. It also discusses 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 estimates, may be the leading cause of global death in 2050.

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