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Updated yesterday at 6:00 am.
What is the discovery?
Ten years ago, Roche researchers examined 45,000 molecules to see whether they were effective against a type of bacteria. Acinetobacter, some strains of which are particularly deadly because they are resistant to multiple antibiotics. One of these molecules, called zosurabalpin, has been shown to be very effective at killing bacteria Acinetobacter that are resistant to common antibiotics.
PHOTO FROM ROCHE WEBSITE
The bacteria Acinetobacter is of the “Gram negative” type, which means it has two protective cases. Zosurabalpine prevents the transport of molecules essential to the structure of the outer membraneAcinetobacer, so-called “lipopolysaccharides”. Without this in the outer membrane, the bacteria die.
“This is a major breakthrough,” said the Roche microbiologist.
Zosurabalpine was introduced as the first new class of antibiotics against gram-negative bacteria in 50 years. For what ?
PHOTO PROVIDED BY CHRISTIAN LAVALLÉE
Christian Lavallée, microbiologist and infectious disease specialist at Maisonneuve-Rosemont Hospital
Dr. Bradley acknowledges that there are other inhibitors of lipopolysaccharide transport. “But zosurabalpine is the only drug that works against itAcinetobacter “, he is arguing.
Could Zosurabalpine be effective against other bacteria?
The transport of lipopolysaccharides differs slightly from one gram-negative bacterium to another. It would therefore be necessary to adapt the structure of zosurabalpin to other bacteria. Roche would not specify whether it was working on this, but Mr Bradley pointed out that it is now well established that targeting the transport of lipopolysaccharides is a promising strategy for the development of new antibiotics.
The study published in Nature states that zosurabalpine, however, did not work against two other bacteria, including Escherichia coli.
What are the chances of success for the next research steps on zosurabalpine?
Roche has started a Phase 1 human clinical trial to assess its toxicity. Mr Bradley is confident that his animal models are “very powerful for evaluating antibiotics”. But Dr. Lavallée estimates that of the antibiotics that work in animal models, a very, very small minority ultimately also work in humans.
Have other similar molecules already reached the same stage?
Yes, murepavadin, another molecule that disrupts the transport of lipopolysaccharides in the outer membrane of a gram-negative bacterium. Pseudomonas aeruginosa. The Swiss company Polyphor has achieved positive results with phase 1 and 2 clinical trials in humans and launched a phase 3 clinical trial in 2019, the last before commercialization. Researcher Ignacio Martin-Loeches from Trinity College Dublin was involved in this work, but it failed. “We observed in Phase 3 that murepavadin was toxic to the kidney in humans. Therefore, the clinical trials were stopped. We are now trying to use it in an aerosol against cystic fibrosis-related infections. »
A Harvard University biochemist who co-authored the other study Nature Regarding zosurabalpine, Dan Kahne believes that murepavadin is “promising,” but its mechanism of action on lipopolysaccharides is “less well characterized.” “Murepavadin has a different structure than zosurabalpine,” says Kahne. This could explain its different effects, particularly its toxicity to the kidney.
Dr. Martin-Loeches points out 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 effects do bacteria have? Acinetobacter resistant to antibiotics?
They are very rare in Canada, according to a study conducted by Dr. Lavallée co-signed study from 2019 Journal of Antimicrobial Chemotherapy. “We followed suit in the mid-2010sAcinetobacter in Quebec resistant to the antibiotic carbapenem, but we stopped because it wasn’t a big problem. There have been some outbreaks in the Quebec region that were likely linked to soldiers going to Afghanistan. »
But in several poor countries, particularly in Asia and North Africa, the problem is even more glaring. Because of its resistance to carbapenem, it is on the World Health Organization’s “critical” list of three drug-resistant bacteria, all of which are gram negative, said Roche’s Mr. Bradley. “We know that microbes don’t respect borders,” he says.
Are there clinical advances in the fight against drug-resistant bacteria?
“In the last decade, there have been several new antibiotics that are effective against antibiotic-resistant bacteria, including certain molecules that destroy the enzyme [qui permet aux bactéries de résister à l’antibiotique carbapenem]says Dr. Lavallée. But they are not available here. In my opinion, the Canadian market is not large enough for companies to apply for approval. You must use a special access program, but there will be delays. »
Learn more
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25 Number of related deaths Acinetobacter Carbapenemase enzymes that are resistant to antibiotics were produced in Canada between 2010 and 2016
SOURCE : JOURNAL OF ANTIMICROBIAL CHEMOTHERAPY
2363 Number of deaths related to Acinetobacter in 2015 in Europe produced carbapenemase enzymes that are resistant to antibiotics
SOURCE : LANCET INFECTIOUS DISEASES
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