Phage make a big comeback in the medical world to fight against bacteria resistant to antibiotics

Antibiotic-resistant bacteria – super-bacteria – are medical monsters of our own design. Recognized by years of abuse and overuse of antibiotics, superbugs require new weapons to treat them. Viruses chasing bacteria, called phages, have become potentially powerful tools in this fight. They have successfully caught vicious infections in a psychologist who has caught a superbug on vacation and a patient with cystic fibrosis in London.

The cases are the most dramatic moments of Western renaissance through phage therapy in Western renaissance. More than a century after its beginnings, phage therapy has a moment. And the researchers hope the moment will last long enough for this to become not only a reliable weapon in our war against superbugs, but also potentially a tool that could do everything from administering anticancer drugs to certain parts of the body to the security of our food supply. .

Just a few decades ago, phages were largely forgotten in the West – but were still used frequently by East Block physicians. Alexander "Sandro" Sulakvelidze, a Georgian researcher, was informed of the disparity of knowledge during a fellowship at the University of Maryland in the 1990s. Sulakvelidze came across his mentor, who had just lost a patient. a drug-resistant infection. When Sulakvelidze asked why the phages had not worked, his mentor asked him what he was talking about.

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

Almost thirty years later, Thomas Patterson lived. The psychologist at UC San Diego caught a vicious stomach virus while traveling to Egypt. When he took a turn for the worse, the blood tests in San Diego revealed that he was fighting Acinetobacter baumannii, a bacterium nicknamed Iraqibacter for its proliferation in the Iraq conflict.

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

Isabelle Carnell is also alive. A patient with cystic fibrosis in London, Carnell's double lung transplant had caused an infection by Mycobacterium abscessus, another superbug. A team, led by Graham Hatfull of the University of Pittsburgh, has also begun phage treatment for Carnell. It was the first time that genetically modified phages were used for treatment, and the first time phages were used against an infection of the genus mycobacterium, which includes tuberculosis, one of the most deadly diseases on the planet. 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. In 2018, inspired in part by Patterson's recovery – detailed in a memoir co-authored by Strathdee with Patterson titled 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.

Superbugs and scorched earth

Strathdee thinks that the main obstacle to phage therapy was his poor fortune to discover before penicillin, in 1917. (The discoverer of this phage therapy, Felix of Herelle, was very unloved, did not find it. not help.) – spectrum, ability of scorched earth to eliminate large bands of different bacteria, the phage – which could attack only one specific bacterium at a time – was considered less useful. Continued research and the use of phages in eastern bloc countries such as Poland and Georgia have helped put the nail in the coffin; the geopolitical bias has made the search for phage for communists.

The specificity that once made phages seem less desirable is now their greatest attraction. By using too many antibiotics, humanity has unwittingly turned the tide in an evolutionary arms race, leaving behind the most potent and drug-resistant bacteria. The phage is now a potentially powerful weapon against these so-called superbugs.

Hatfull says that phages have been locked in an invisible war with bacteria for potentially 3 billion years, preceding most of the life forms we see today and preceding bacteria just as long. The typical phages described in science books and as mascots of the phage centers belong to the family. Myoviridae. Resembling the child in love with a spider and a syringe, they have a thin body surmounted by a "head" similar to a Dungeons & Dragons die and end with a protrusion that injects their genetic material into the bacteria. The virus replicates inside the hijacked host, eventually destroying the bacteria during its escape. This process is called the lytic cycle, and hunter-killer phages are called lytic to distinguish them from other phages that do not kill their prey.

Working together as a cocktail of phages, lytic phages can target and destroy superbugs. When bacteria begin to resist phages, biologists can genetically modify phages to better attack bacteria. Phage can even work with antibiotics, applying progressive pressure on both sides. Bacteria must "choose" the substances to which they become resistant, making them vulnerable to the other method of treatment.

"We do not know enough about this kind of synergy, "says Strathdee. But further study can reveal which phages work best with which antibiotics, thus opening up new methods of treatment. "Many of us do not think phages will replace antibiotics. We think that they are going to be a complement to antibiotics. "

Mzia Kutateladze, director of the Eliava Institute in Tbilisi, Georgia, is eager to see phage therapy gain strength and gain resources in the West. While a few decades ago Georgian scientists like Kutateladze and Sulakvelidze were perceived as indifferent to the use of phages, they now find a new acceptance.

"I am really proud to be able to say with the Georgians that we have a lot of international patients coming to us," said Kutateladze. "And we have very good results with very, very desperate and chronic infections."

Custom bacteria killers

Although promising, phage therapy has drawbacks.

"Specificity is a double-edged sword, "says Graham Hatfull by phone. This is beneficial for superbugs and to avoid side effects. But this precision has a price: a phage that works for one strain of superbug in one patient may not work for another strain. The diagnosis of the good pathogen becomes absolutely critical because phages not designed to attack the bacteria to be treated are useless in said treatment.

Strathdee believes that a giant, open-source phage library is essential for making phage therapy valuable. Scientists and doctors can use the library to match phages and bacteria, ensuring faster treatment. With enough genomic information on bacteria and phages – and a sufficient training package – Hatfull imagines a world where machine learning improves therapies. We could sequence the pathogen, integrate genomics with the algorithm and find out which phages mix to form the most effective cocktail.

Jean-Paul Pirnay, a researcher at Queen Astrid Military Hospital in Brussels, goes even further in this vision. Pirnay thinks that the synthetic natural phages, on which Queen Astrid works, could help alleviate the problem of specificity. A system for producing custom-made iterations of natural phages would mean rapid adaptation to particular pathogens and would eliminate the expense of storing massive stocks of phages. Finally, Pirnay imagines a world where phages do not exist in nature – really custom-made viruses – are designed with the help of artificial intelligence to be as effective as possible, an infinite toolbox.

Adding fuel to the fire is a new investment by pharmaceutical companies as genetically modified phages can be patented. Johnson & Johnson has signed a multi-million dollar partnership with Locus Biosciences, a North Carolina-based company specializing in the use of boutique phages for injecting CRISPR-Cas3 into bacteria. CRISPR-Cas3 is often compared to Pac-Man: once inside the bacteria, it shreds the DNA of the bacteria as a blue ghost and kills it.

Genus's genetically modified phages help to alleviate one of the problems posed by phage treatment: lytic phages do not always kill each bacteria. Locus can design the phages so that they have a more effective "Depth of Destruction Profile", which helps ensure that anything that is hunted to the phage is killed.

The use of phages as targeted biological syringes is also conceivable. "In theory, you can deliver different types of enzymes that act in different ways," says Joseph Nixon, vice president of business development at Locus. Nixon is considering the use of phages to target cancer targets and – what he calls the "Holy Grail" – targets of the central nervous system.

Theoretically, phages could be used to target bacteria in other ways – potentially increasing their pathogenicity instead of killing them. Fortunately, it's unlikely, writes Pirnay. He says there are more practical methods available for the militarization of bacteria, including the CRISPR-Cas tools.

Phages of thought (and food)

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

Phage, which target bacteria that cause food-borne illnesses, are not only effective at killing pathogens, but are also kosher and halal certified, non-genetically modified, listed by the Organic Materials Review Institute, and are less abrasive than the commonly used chemical methods. Phage are sprayed on food, taking advantage of the infrastructure already in use and costing a bit more than food safety chemicals, but are considerably cheaper than other non-chemical protections such as radiation and food. pasteurization at high pressure.

For similar reasons related to health and the fight against superbugs, phages also have veterinary applications; Targeted phage therapies to treat sick animals can eliminate the excessive use of antibiotics in animal feed.

According to Intralytix, phages have applications in environmental sanitation and as probiotics: killing bad things, keeping good ones. And the company recently announced a partnership with Ferring Pharmaceuticals and the Eliava Foundation, a non-profit organization in Georgia, which is a separate entity of the Institute, to undertake research on reproductive health and women's health. . Researchers believe that phages could help manage bacterial vaginosis, wrote Sulakvelidze in an email to The edgeand the treatment of diseases related to pregnancy. Once again, the specificity of phages is essential. they could attack the "bad" bacteria without destabilizing the invisible ecosystem of the body.

Sulakvelidze imagines a near future where phages – for food security, or perhaps dietary supplements – are readily available in the West, perhaps even at the counter, as in his native Georgia.

Obstacles of the bacteria hunter

All of the above work – the search for the Super Bug, the research and use of genetically modified phages, as well as their application in agriculture and over-the-counter uses – are ongoing and will continue probably to grow as superbugs continue to kill and new uses for phages are discovered. And while all this is promising, phage research poses real challenges.

We are entering a long-standing arms race that will continue well after our demise. The recent discovery of a CRISPR-Case defense that steals the phage of replicating machines is only one of the many ingenious defenses we will undoubtedly encounter if we continue to fight superbugs. . The phage treatment will have to find ways to overcome these bacterial defenses to remain effective.

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 we can find applications. Poorly conducted clinical trials had already paralyzed the ground, and hasty precipitation without further understanding could propel it to the bottom. According to Kutateladze, people who use phages need to know how to use them, what phages are needed, and how they work in general.

The biggest challenge of all, however, may be the perception – but it changes quickly.

Strathdee was invited to tell her story and that of her husband at the annual meeting of the Infectious Diseases Society of America. At the very end of the conference on a Sunday morning, when many of them have usually returned home, hundreds of people have invaded the room to hear the harrowing story. Strathdee said that many people were crying and then went to see her afterwards to express their new interest in phages.

"We're seeing more excitement than ever before because our backs are against the wall, "said Strathdee. The superbugs threaten the world; we have interfered in the delicate balance between humanity, viruses and bacteria.

"In the case of my husband, strangers from around the world came to give phages to heal him. And if we can do it for one man, we can do it for the planet. "