In December 1945, during his Nobel Prize acceptance speech Following the discovery of penicillin, Dr. Alexander Fleming warned that bacteria could become resistant to the drug if exposed to non-lethal amounts. “It is not difficult to make microbes resistant to penicillin in the laboratory by exposing them to concentrations that are insufficient to kill them, and the same has happened on occasion in the body,” explained the scientist.
His warning was foreboding. Today many bacteria are resistant to multiple antibiotics, and consequently difficult to treat in patients. This occurs because, when antibiotics are used, the bacteria generate ways to eliminate, sabotage, or circumvent the effects of the medicine.
The consequences for human health are serious. An estimated 700,000 people die each year from antibiotic-resistant microorganisms. The World Health Organization (WHO) predicts that if nothing changes, by 2050 the figure will reach 10 million deaths annually.
To make matters worse, we are not developing new antibiotics fast enough. According a recent WHO review, of the 43 antibiotics in development, none is a novel drug that adequately targets a priority group of resistant bacteria. In fact, no new type of antibiotic has been on the market since the 1980s that tackles the most troublesome bacteria, most of them in a group that microbiologists call gram-negative.
WHO predicts that if nothing changes, by 2050 the death toll will reach 10 million deaths annually
“The fruits most within reach have already been harvested. Now it is more complicated and difficult to discover new antibiotics, ”says Guy-Charles Fanneau de la Horie, CEO of Pherecydes Pharma, a French biotechnology company.
An alternative to searching for new drugs is to use spacecraft-shaped viruses called bacteriophages (or phages) that feed on bacteria. When phages come into contact with bacteria, they inject DNA into them and replicate within them. Soon, virus accumulations erupt to infect more bacteria.
De la Horie’s company, Pherecydes, focuses on the production of these phages and their administration to patients infected with drug-resistant bacteria. Their phages kill three species of bacteria known for their resistance to first-line antibiotics: Staphylococcus aureus, the Escherichia coli and the Pseudomonas aeruginosa. All three are responsible for many drug-resistant infections contracted in hospitals, where the most dangerous microbes reside, De la Horie notes.
Injecting phages into patients should be perfectly safe, because they do not attack human cells. And, unlike many antibiotics, which affect multiple species of bacteria, phages are more accurate and don’t kill “good” gut microbes. “They are very specific,” notes De la Horie. “For example, a phage that kills the S. aureus will have no effect on Pseudomonas.
Being a higher precision weapon, the correct phage must be chosen carefully to kill the corresponding bacteria. For this reason, Pherecydes has created laboratories to evaluate samples from sick people, analyze bacteria that cause problems and choose a specific phage to kill them.
“We have discovered a small number of phages that we call ‘superphages’ because they are active against a whole series of strains within the same species,” explains the specialist. If a patient has Pseudomonas aeruginosa, a dangerous microbe that often attacks patients connected to a respirator, they are given phages that kill more than 80% of the strains.
Phage therapy has not yet been authorized by the European Medicines Agency, but Pherecydes has treated patients infected with drug-resistant bacteria after knee or hip surgery, using so-called “compassionate use”, when other options treatment have failed. These infections are especially difficult to treat with antibiotics. The problem is not minor. “Between 2% and 5% percent of hip or knee replacements become infected,” says De la Horie.
So far, the company has used phages to treat more than 26 patients, the majority in the main hospital in Lyon, France. For example, reports show that he has treated three elderly patients with S. aureus infection in knee replacementas well as a patient with a persistent Pseudomonas infection. A trial on joint infections after hip or knee surgery is planned to be launched later this year.
Of the 43 antibiotics in development, none is a novel drug that adequately targets a priority group of resistant bacteria
The company has also developed sophisticated phage production processes with the support of a project called PhagoProd. They are being manufactured in liters, but the plan is to increase to tens of liters. A single milliliter in a vial can contain 10 billion phages.
And what’s even better: when phages are injected into a patient or applied to an infected tissue, they multiply inside the bacteria they are targeting, thereby increasing the amount of virus ready to kill them. . “Once the phages are put in the presence of the bacteria, it should not be necessary to inject more, because they will multiply by themselves,” explains De la Horie.
The CEO of Pherecydes hopes that a large-scale trial with patients can begin in 2023. “We think that our products could be on the market at the earliest in 2024, or maybe 2025,” he says.
It’s better to prevent than to cure
One of the problem microbes, Pseudomonas aeruginosa, is among the targets of a project called BactiVax, which also addresses the problem of antibiotic resistant infections. Rather than using phages or other methods to treat infections once they appear, BactiVax researchers are looking to vaccines.
The Pseudomonas they are a plague for patients in intensive care, those with chronic obstructive pulmonary disease (COPD), and those with cystic fibrosis.
The bacteria can cause chronic and severe infections. “It is quite common, and sometimes it is not really harmful,” says Irene Jurado, a doctoral student at University College Dublin, in Ireland, “but it can be a problem for people with previous pathologies.”
If a child with cystic fibrosis becomes infected with some strains when they are five or six years old, the microbe can remain in their lungs for the rest of their life, making it difficult for them to breathe and causing serious illness, adds the researcher.
Pseudomonas has a very long genome that gives it great flexibility to adapt to different difficulties, something about which Jurado has recently written. This gives you a special ability to develop resistance to antibiotics. For this reason, researchers have been trying for decades to create a vaccine against the bacteria, without success.
Jurado is investigating the proteins the pathogen uses to attack lung cells. This could provide critical components for a vaccine, in the same way that the SARS-CoV-2 spike from Covid-19 vaccines instructs our immune systems.
“We are trying to see what immune responses are needed to protect people from infection,” explains Siobhán McClean, an immunologist at University College Dublin, Ireland, who is leading the BactiVax project. The proteins that bacteria use to adhere to our cells are often good targets for vaccines. For example, the pertussis vaccine uses five different proteins that bacteria attach to the cells that line the throat.
Unfortunately, the bacterium is a tougher enemy than the covid-19 virus, as it does not have one, but dozens of proteins on its exterior. This means that what should be included in a vaccine is less obvious in the case of Pseudomonas than in the pandemic virus, in which the target is the spicule.
But researchers believe that a vaccine is worth the effort. “Our idea is that we can get a vaccine to prevent infection. That’s better than constantly trying to treat (problem infections) with antibiotics, ”says McClean. “We only have last resort antibiotics left, and when they run out, we will be at a dead end.”
Translation of NewsClips.