A step forward in countering antibiotic resistance

Researchers from Harvard and the pharmaceutical firm Roche presented encouraging results at the beginning of January for a new antibiotic, zosurabalpin. Their discovery, published in two articles in Naturebrings the problem of antibiotic resistance back into the spotlight.

What is the discovery?

Ten years ago, Roche researchers evaluated 45,000 molecules to see if they were effective against a type bacteria. Acinetobacter, some strains of which are particularly deadly because they are resistant to several antibiotics. One of these molecules, called zosurabalpin, has been shown to be very effective in killing bacteria Acinetobacter which are resistant to current antibiotics.

“This new molecule is not affected by existing antibiotic resistance mechanisms,” says Kenneth Bradley, a researcher at Roche in Switzerland, who is the lead author of one of two articles published on the subject in Nature.

The bacteria Acinetobacter is of the “Gram negative” type, which means that it has two protective envelopes. Zosurabalpin prevents the transport of molecules essential to the structure of the outer membrane ofAcinetobacer, called “lipopolysaccharides”. Without these in its outer membrane, the bacteria dies.

“This is a major breakthrough,” said the Roche microbiologist.

Zosurabalpin was introduced as the first new class of antibiotics against Gram-negative bacteria in 50 years. For what ?

Christian Lavallée, microbiologist and infectious disease specialist at Maisonneuve-Rosemont hospital, tempers this assertion. “It’s too early to say, these are only results on an animal model. Articles like these are published regularly. We must wait to have the results in humans. »

Dr. Bradley acknowledges that there are other inhibitors of lipopolysaccharide transport. “But zosurabalpin is the only one that works againstAcinetobacter “, he argues.

Could zosurabalpin be effective against other bacteria?

The transport of lipopolysaccharides is slightly different from one Gram-negative bacteria to another. It would therefore be necessary to adapt the structure of zosurabalpin to other bacteria. Roche did not want to specify whether it is working on it, but Mr. Bradley points out that it is now well demonstrated that targeting the transport of lipopolysaccharides is a promising strategy for the development of new antibiotics.

The study published in Nature specifies that zosurabalpin did not, however, work against two other bacteria, including Escherichia coli.

What are the chances of success for the next stages of research on zosurabalpin?

Roche has launched a phase 1 human clinical trial to evaluate its toxicity. Mr. Bradley is confident that his animal models are “very powerful for evaluating antibiotics.” But the D^r Lavallée estimates that among the antibiotics that work in animal models, a very, very small minority ultimately works for humans.

Have other similar molecules already reached the same stage?

Yes, murepavadin, another molecule that interferes with the transport of lipopolysaccharides in the outer membrane of a Gram-negative bacteria, Pseudomonas aeruginosa. Swiss company Polyphor has had positive results with phase 1 and 2 human clinical trials and launched a phase 3 clinical trial in 2019, the last before commercialization. Researcher Ignacio Martin-Loeches, from Trinity College in Dublin, participated in this work, which ended in failure. “We observed in phase 3 that in humans, murepavadin was toxic to the kidney. So the clinical trials were stopped. We are now trying to use it in an aerosol for infections linked to cystic fibrosis. »

A biochemist from Harvard University who co-authored the other study Nature on zosurabalpin, Dan Kahne, believes that murepavadin is “promising”, but that its mechanism of action on lipopolysaccharides is “less well characterized”. “Murepavadin has a different structure from zosurabalpin,” says Kahne. This could explain its different effects”, in particular its toxicity for the kidney.

The D^r Martin-Loeches notes that some antibiotics currently used against antibiotic-resistant bacteria, such as vancomycin, are also toxic to the kidneys. “These are molecules that would not be approved now. » Vancomycin was discovered in 1953 and commercialized in 1954.

What is the impact of bacteria Acinetobacter resistant to antibiotics?

In Canada, they are very rare, found a study co-signed by Dr.^r Lavallée in 2019 in the Journal of Antimicrobial Chemotherapy. “In the mid-2010s we followed theAcinetobacter resistant to the antibiotic carbapenem in Quebec, but we stopped because it is not a big problem. There have been a few outbreaks in the Quebec region, probably linked to soldiers who went to Afghanistan. »

But in several poor countries, particularly in Asia and North Africa, the problem is more glaring. It is part of a World Health Organization “critical” list of three drug-resistant bacteria, all Gram negative, because of its resistance to carbapenem, said Mr. Bradley, of Roche. “We know that microbes do not respect borders,” he says.

Is there clinical progress in the fight against drug-resistant bacteria?

“In the last decade, there have been several new antibiotics effective against antibiotic-resistant bacteria, including certain molecules that destroy the enzyme [qui permet aux bactéries de résister à l’antibiotique carbapenem]said the D^r The valley. But they are not available here. In my opinion, the Canadian market is not large enough for companies to request approval. You have to use a special access program, but there are delays. »