Transmission electron micrograph of multiple bacteriophages attached to a bacterial cell wall.
| Photo Credit: Graham Beards (CC BY-SA)
If one has a urinary tract infection, for instance, the pathology lab will identify the bacterium to be, say, Escherichia coli. It will also determine the pathogen’s sensitivity to over a dozen antibiotics. It is fine if the bacterium is sensitive to many or all of the drugs. The nightmare scenario is when it is resistant to all of them.
Increasingly, antibiotics don’t work because the bacteria have developed resistance. It is estimated that globally about five million people are dying of conditions related to antimicrobial resistance (AMR) each year. This may double by 2050. It is a silent pandemic.
What is the solution? Largely, pharmaceutical companies have lost interest in developing new antibiotics. Whereas a drug for cancer is used for a long time, antibiotics are given for just a few days. Also, due to the problem of AMR, new antibiotics are used as sparingly as possible to prevent the development of resistance. Therefore there is no financial incentive for companies to work on new antibiotics. There is some drug development happening but probably not enough to address the AMR problem.
Bacteriophages are ‘good viruses’ that naturally prey on bacteria. They are all around us, in the water, in the soil, in our gut, on our skin, etc. There are believed to be 10-times as many phages as bacteria on the earth.
Phages were beginning to be used against bacterial infections about a century ago, but antibiotics superseded them once they were discovered. Unlike an antibiotic, which may be able to kill many species of bacteria, phages may only kill a few strains of a particular bacterium. Therefore only countries in the Soviet bloc, cut off from the antibiotics, continued to use them. An institute in Tbilisi, Georgia, with over 100 years of experience, is famous for its phage expertise. Due to AMR, the rest of the world is now rediscovering phages and relevant research is ongoing in many countries.
Phages have been used for burns, foot ulcers, gut infections, respiratory infections, urinary tract infections, etc. There are two main strategies that have been used. One, isolate the bacteria from the infected tissue, check which phage works against it in the lab, grow more of that phage and administer it to the patient. These phages may come from a phage bank of one’s own or in very serious cases one may even ask phage banks elsewhere in the world for help. These are natural phages. Then there are genetically engineered phages, which have been modified in the lab to, say, expand the variety of bacteria they can kill.
To the extent that phages are being used as drugs, they have a unique feature. Bacteria can evolve to be resistant to an antibiotic; likewise, bacteria can evolve to be resistant to a phage. The unique part is that the phages, too, can evolve to avoid the bacterial resistance. The drug is not a constant but an evolving entity. This is therefore a headache for the regulators, since no drug has ever been approved that evolves. Further, since phages are very specific to bacteria, one phage will not work against a large fraction of, say, foot ulcers, as happens with an antibiotic (until we have to consider AMR). So it is also challenging to conduct randomised controlled trials when the drug needed for each patient may be different.
The world is desperate for new treatment modalities for AMR. Thus far, no government in the Western world has approved a phage as a drug. But they may allow patients to access phages in the form of “compassionate use”, “emergency-use expanded access” or “special access” routes. These are often approvals for single, named patients who are in desperate need. Yet another route, used in Belgium for instance, is the “magistral route” where particular pharmacies can ‘compound’ a phage specifically for a particular patient.
The regulatory headache may be solved if the following scenario, which Jean-Paul Pirnay and colleagues in Belgium are researching, works out. Create a device in which all of the following steps can be conducted: isolate the bacteria from an infection, sequence its genome, use AI to determine which phage genome is the most likely to work, create the phage from scratch in the device, and administer it to the patient on the spot.
In such a scenario, the phage wouldn’t be regulated as a drug. Instead, the device would be regulated. And the device would only contain routinely used molecules such as nucleotides and enzymes that would be used to assemble the phage.
The scale of AMR is such that we need many large initiatives to try and tackle it. If a group of microbiologists is looking for a grand challenge that uses AI, surely the Pirnay route is one worth exploring?
Gayatri Saberwal is a consultant at the Tata Institute for Genetics and Society.
Published – June 08, 2025 05:30 am IST
