These viruses that fight superbug are making their comeback

Antibiotic-resistant bacteria – super-bacteria – are medical monsters of our own design. Enduring years of abuse and abuse of antibiotics, superbugs require new weapons to treat them. Bacterial hunting viruses, called phages, have become potentially effective tools in this fight. They were successfully sacrificed in malignant infections by a psychologist who caught a superbug on vacation and a patient with cystic fibrosis in London.

Falls are the most dramatic moments of the revival of phage therapy in the West. More than a century after its beginnings, phage therapy has a moment, And the researchers hope that this moment will last long enough to constitute a reliable weapon in the fight against the superbugs, but also an instrument able to do everything possible so that the anti-cancer drugs cover parts of the body and make our food supplies more safe.

Just a few decades ago, phages were largely forgotten in the West – but were still frequently used by East Block physicians. Alexander "Sandro" Sulakvelidze, a Georgian researcher, discovered the knowledge deficit during a scholarship given at the University of Maryland in the 1990s. Sulakvelidze met with his mentor, who had just lost a patient because of his illness. a drug-resistant infection. When Sulakvelidze asked why the phages were not working, his mentor asked him what he was talking about.

"It's one of the moments in life that really struck me," says Sulakvelidze on the phone. "The father, brother, husband and friend of someone just died in the most developed country in the world … died really unnecessarily, probably from a simple infection that would have probably been treated in Georgia. "

Almost thirty years later, Thomas Patterson lived. The UC UC San Diego psychologist contracted during a vacation in Egypt, malignant stomach ache. As he got worse, blood tests in San Diego showed that he was fighting Acinetobacter baumannii, a bacterium nicknamed Iraqibacter because of its spread in the Iraq conflict.

Iraqibacter is an example of "superbacteria", an antibiotic-resistant bacterium. Desperate, his wife – epidemiologist Steffanie Strathdee – was involved in medical research and found trials on phage therapy. She immediately called other doctors around the world. The help that resulted saved her husband's life.

Isabelle Carnell lives too. The double lung transplant of Carnell, a patient with cystic fibrosis in London, led to an infection Mycobacterium abscessus, Another superbug. A team led by Graham Hatfull of the University of Pittsburgh also started phage treatment for Carnell. This was the first time that genetically engineered phages were used for treatment and, for the first time, phages were used to control the infection. mycobacterium, which includes tuberculosis, one of the world's deadliest diseases. In six months, the infection had been repelled.

In 2010, Texas A & M University opened the Center for Phage Technology. The US Navy Medical Research Center began seriously studying phages a year later. Inspired in part by Patterson's recovery in 2018 – detailed in a memoir written by Patterson titled Strathdee The perfect predator – The San Diego UC has founded the Center for Innovative Applications of Phage and Therapeutics (IPATH). Strathdee is now co-director of IPATH.

Strathdee believes that the misfortune, discovered in 1917 before the discovery of penicillin, was the main obstacle to phage therapy. (Felix Herelle, widely rejected discoverer of phage treatment, has not helped.) Spectrum, the ability of burnt earth to remove large amounts of various bacteria, the phage – which could not be safe. attacking only one bacterium at a time – was considered less useful. considered. Continued research and the use of phages in eastern bloc countries, such as Poland and Georgia, have put the nail in the coffin. Geopolitical bias has made research a phage for communists.

The peculiarity that makes phages seem less desirable is now their greatest attraction. With the excessive use of antibiotics, humanity has unconsciously turned the tide in an evolutionary arms race and left behind the most powerful and drug-resistant bacteria. Phage is now a potentially effective weapon against these so-called superbugs.

Hatfull says that phages have been included in an invisible war against bacteria on potentially three billion Years older than most life forms we see today and just as old as bacteria. The typical phages described in scientific books and as a mascot of phage centers come from the family MyoviridaeThey look like a spider and a syringe and have a slim body with a "head" similar to this one. dungeons die and end up in a thread that injects their genetic material into the bacteria. The virus replicates in the removed host and eventually destroys the bacteria when they escape. This process is called a lysis cycle, and Hunter's killing phages are called lyses to distinguish them from other phages that do not kill their prey.

When lytic phages act together as a cocktail of phages, they can attack and destroy the superbugs. When bacteria begin to resist phage, biologists can genetically modify the phage to better attack the bacteria. Phage can even collaborate with antibiotics by exerting evolutionary pressure on both sides. Bacteria must "choose" what they need to become resistant and are subject to the other method of treatment.

"We do not know enough about this type of synergy, "said Strathdee, however, other studies may show which phages work best with which antibiotics and thus open up new therapeutic methods. 39 among us do not believe that phages will ever replace antibiotics and we believe that they will complement antibiotics. "

Mzia Kutateladze, director of the Eliava Institute in Tbilisi, Georgia, is delighted to see that phage therapy is gaining ground and resources in the West. While Georgian scientists such as Kutateladze and Sulakvelidze were considered twisted a few decades ago because of the use of phages, they are increasingly accepted.

"I can say with pride to Georgians that many international patients come to see us," said Kutateladze. "And we have very good results with very, very desperate and chronic infections."

Although phage therapy is promising, it has drawbacks.

"The peculiarity is a double-edged sword, "says Graham Hatfull on the phone, which is beneficial for superbugs and for avoiding side effects, but this has a price: a phage that works for a Superbug strain in a patient may not The diagnosis of the good pathogen becomes absolutely critical because phages that are not designed to attack the bacteria to be treated are useless in this treatment.

Strathdee believes that a huge open source phage library is the key to making phage therapy valuable. Scientists and doctors can use the library to match phages and bacteria for faster treatment. With enough genomic information on bacteria and phages, and enough exercise, Hatfull imagines a world where machine learning will improve therapies. You can sequence the pathogen, integrate genomics into the algorithm and determine the phages to mix in the most effective cocktail.

Jean-Paul Pirnay, a researcher at the Queen Astrid Military Hospital in Brussels, goes even further with this vision. Pirnay thinks that the synthetic natural phages used on Queen Astrid can mitigate the problem of specificity. A system for producing personalized iterations of natural phages would allow rapid adaptation to certain pathogens and reduce the cost of storing massive phage stocks. Finally, Pirnay imagines a world in which phages do not exist in nature – really Custom viruses – are made as effective as possible with the help of artificial intelligence, an infinite toolbox.

The addition of fuel to the fire is a recent investment by pharmaceutical companies because genetically modified phages can be patented. Johnson & Johnson is working in partnership with Locus Biosciences, a North Carolina-based company, specializing in the use of shop phages to inject CRISPR-Cas3 into bacteria. CRISPR-Cas3 is often compared to Pac-Man: once it's in the bacteria, it breaks down the DNA of the bacteria like many blue ghosts and kills them.

Locus genetically modified phages help mitigate one of the challenges of phage therapy, namely that lytic phages do not always kill each Bacteria. Locus can create a more effective "killing profile" for phages, thus killing all phage hunts.

It is also possible to use the phage as targeted biological syringes. "Theoretically, you can provide all kinds of enzymes to do all kinds of things," said Joseph Nixon, executive vice president of business development at Locus. Nixon imagines that phages are used to identify cancer targets and what he calls the target of the central nervous system.

Theoretically, phages could be used to treat bacteria in other ways – possibly increase their pathogenicity, rather than killing them. Fortunately, it's unlikely, Pirnay writes. He says there are more practical ways to fight bacteria, including CRISPR-Cas tools.

Memories of the senseless death of his mentor's patient remained with Sulakvelidze. He then founded Intrimetix, a Baltimore-based, phage-based company that is perhaps best known today for its food-safe virus applications.

Phage targeting certain bacteria causing foodborne diseases are not only effective in killing pathogens, but they are also kosher and halal certified, non-genetically modified, listed by the Organic Materials Review Institute and less abrasive than the commonly used chemical methods. Phage are sprayed on food using potentially existing infrastructure and cost a bit more than food safety chemicals, but are significantly cheaper than other non-chemical protective measures such as radiation. and pasteurization at high pressure.

For similar health-conscious and anti-superbacteric reasons, phages also have veterinary applications; Targeted phage therapies to treat livestock can eliminate the excessive use of antibiotics in foods.

According to Intralytix, phages have applications in environmental remediation and as probiotics: they kill the bad things and keep the good ones. And the company recently announced a partnership with Ferring Pharmaceuticals and the Eliava Foundation, a non-profit Georgian organization separate from the institute, to launch research on reproductive health and women's health. The researchers believe that phages could help treat bacterial vaginosis, wrote Sulakvelidze in an email. The edgeand the treatment of diseases related to pregnancy. Here again, the specificity of phages is the key; They could attack the "bad" bacteria without destabilizing the invisible ecosystem of the body.

Sulakvelidze envisions a near future in which phages – for food security or perhaps nutritional supplements – are readily available in the West, perhaps even over-the-counter, as in his native Georgia.

All of the work above – looking for super-microbes, research and use of genetically modified phages and their applications in agriculture and OTC applications – are ongoing and will likely continue as super-microbes continue to kill and find new applications through the discovery of phages, and while all this is promising, phage research poses real challenges.

We are entering an arms race long before us and it will be a long time before we disappear. The recent discovery of a CRISPR-Case-defeating phage-killing machine is only one of the many ingenious defense mechanisms we will undoubtedly encounter when we continue to fight against the superbugs . Phage therapy must find ways to overcome these bacterial defenses and maintain their effectiveness.

A current lack of basic knowledge needs to be addressed. The more information we have about phages and their chosen prey, the better we can use them and the more apps we can find. Poor clinical trials have previously blocked the field, and a headless attack without additional understanding could now turn it into a spiral. People who use phages should, according to Kutateladze, know how to use them, what phages are needed and how they work in general.

However, the biggest challenge of all can be perception – but that changes quickly.

Strathdee was invited to share her story with her husband at the annual meeting of the Infectious Diseases Society of America. At the end of the conference, one Sunday morning, while many were returning home, hundreds of people invaded the room to hear the poignant story. Strathdee stated that many people in the audience were crying and coming to see her expressing her new interest in phages.

"We're seeing more excitement than ever before because our backs are clinging to the wall, "Strathdee said," The superbugs are threatening the world, we've compromised the delicate balance of humans, viruses and bacteria.

"In the case of my husband, strangers from all over the world came to donate phages to heal him. And if we can do it for a man, we can do it for the planet. "