Discovery of Antibiotics is one of the major break throughs in the modern health care. Post antibiotic era, studies show that human life expectancy has increased by 20 years. As opposing to this fact, recently antibiotics have also been reported to be reducing the life expectancy due to resistance. Antibiotic resistance is one of the biggest threats humanity is facing at the moment. Bacterium like CRKP have become resistant to colistin, an antibiotic which is carefully prescribed under controlled environments to prevent the creation of another superbug. The scary part with colistin resistance is that, it is quite often used as the last line of defence when other antibiotics have failed.

To understand how serious this situation is, lets take the Panamanian golden frog for example.

Panamanian Golden Frog. (source: Wikipedia)

While you are admiring its beauty, I am sorry to say that they have become extinct in the wild since 2007. This is due to the outburst of Chytridiomycosis. A fungal attack that spreads on its skin, preventing it from breathing and eventually leading it to die. The First break of Chytridiomycosis was discovered in 2006 and by 2007 the species became extinct. Can you imagine a species getting wiped out in such a short span due to an infection? It is still very tough for me to digest it as a fact. Even though Chytridiomycosis is a fungal infection and not bacterial, the point I am trying to make is, deadly infections can happen out of nowhere. Given the current state of things, infections caused by future mutations of superbugs could literally wipe out huge population. To know that the antibiotics which we developed to protect us against such outbursts have started to fail is quite alarming.

For others who are also feeling sad for the Panamanian golden frog, they are not completely extinct yet. Quite a few of them are being clinically preserved in a closed environment and bred. I came to know about this sad story when I was reading The Sixth Extinction: An Unnatural History by Elizabeth Kolbert. I recommend you all to read it and understand how all major extinction events happened in a blink of an eye relative to the evolutionary timeline. After 5 major extinction events and after millions of years of evolution, yet we have survived. Let’s take a minute to appreciate our biological existence.

So what led to this antibiotic resistance?

Antibiotic abuse.

Evolution.

The fact being cheap and easy to store which made antibiotics successful became the reason for its demise. Antibiotics which should be used as a last line of defence were quite abused for simple things like flu and headache. This is bad and this abuse has been going on for a while finally making people resistant due to overuse. Sometimes purely by chance, a few bacteria that escape the antibiotic attack have learnt to become resistant. This learning is passed over making other bacteria also to learn the resistance. Bacteria pass this genetic information not only to its offspring but also to its relatives by touching each other. This is because bacterial DNA is not only stored in its chromosome but also in a protein called Plasmid which freely floats around the bacterial wall. Just by touching another bacterium, they can spread the resistance. So it is passed over quickly than what we can imagine. This passing of genetic information with a touch is brilliant from the evolutionary stand point but it is sad news for us.

Estimated deaths due to antibiotic resistance. (source: statista)

The above chart shows the numbers from a popular prediction which expects a devastating number of 10 million deaths that might occur due to antibiotic resistance by 2050. And it is also predicted to surpass deaths by cancer by a significant margin.

Why Antibiotics may fail?

Though recent antibiotic discoveries like malacidin are brilliant, the journey for a new antibiotic from discovery to consumer production is approximately 10–15 years. With tough FDA regulations and clinical trials becoming costlier, this makes it difficult for the Pharma companies to invest their time and money in antibiotic research. In simple terms it is not lucrative as it used to be for the Pharma companies. Because of this, the number of antibiotics that are being discovered have fallen significantly in the recent years.

The above chart represents the number of antibiotics discovered in each decade since 1930s. You can observe a steep fall after 1980s. Sadly so far in this current decade, discovery of new antibiotics is much lesser than what we discovered in 1940s.

The main reason why antibiotics may fail completely because they are fighting against evolution. The stronger the antibiotics become, the bacteria will eventually learn to become resistant. It is very difficult to go against the evolutionary cycle because life finds its own way.

While things are getting pretty serious, there is still some hope left.

Phage Therapy

Enter into the world of Bacteriophages. Bacteriophages or phages(how they are mostly called) are viruses which attacks and kills bacteria. Phages first enters into a bacterium by breaking through its wall, and then it attacks the bacterium by turning it into factory producing more phages. When the attack is beyond a certain threshold the bacterium simply explodes and dies. The new phages which got produced, goes and attacks the other bacterium making it sort of a chain reaction. Phage attacks are brutal.

Phages and bacteria have been fighting against each other for many million years and much longer than we can imagine. Phages are present in sea, dirt, sewers, animal intestines and almost every where on the planet. New phages are discovered almost every day. The number of phages in aquatic systems alone are estimated somewhere around 10⁴–10⁸ virions per ml. That’s quite a significant number. Good news is, along with the bacteria they are also evolving and becoming stronger to kill it.

If phages can kill bacteria, evolve with them as they get stronger, why not use them to treat bacterial infections? That is exactly what phage therapy does. Patients treated with phage therapy are given a mock-tail containing a mixture of different phages which are identified to kill the bacteria causing the infection.

Selecting the phages that can be used for treatment in humans is a significant process. First step would involve selecting phages which are not harmful for humans. Then the phages to be used against a specific bacterial infection is selected. This is done by spreading a layer of disease causing bacteria in a petri-dish and then dropping solutions containing phages on it.

Petri dish experiment to identify phages. source: researchgate.net.

In the above image, you can see the phage solution dropped on the area marked as B has shown some lytic activity. This process is repeated for a while until the results are promising. Also phages which are used for treatments are found not to be affecting your gut-flora which is not the case with antibiotics. Often after an antibiotic course, probiotics might be prescribed to help your gut-flora.

Phage therapy has its roots way to back to a time even before antibiotics were discovered. Antibiotics took of the race simply because it was cheap and easy to transport. Right now if you want to undergo phage therapy, you have to either travel to Russia, Poland or Georgia.

Like every other clinical treatment, phage therapy has its own set of problems .

Phages are mostly cultured in banks which makes it harder for regulatory testing and it is quite expensive to bank phages.

Given the roots of phage therapy being not clearly known, patent-ting a phage is quite a debatable subject. This is a huge let down for Pharma companies given their mode of business generally works around claiming the rights for their ownership.

Documentary explaining phage therapy.

Apart from being a potential alternative to antibiotics, researching about phages have also helped us move a little closer to gene editing in living cells. Phages despite being brutal in killing bacteria, some bacteria have evolved and put together a brilliant line of defence like CRISPR. CRISPR is a family of DNA sequence found in some bacteria. Its contains the DNA copies of phages which have attacked in the past. They use this to identify a phage by comparing its DNA against the DNA it has stored in the CRISPR sequence. Most bacteria with CRISPR sequences can destroy a phage before it starts attacking it. This process is done by a protein called CAS-9 which the bacterium releases incase of a potential phage attack. The CAS-9 protein compares the DNA of the foreign object with CRISPR database to identify the phage and there by tearing it apart making it impossible for the phage to start its attack. The beauty of CAS-9 is, it can also add a new phage’s DNA to the CRISPR database, which involves editing the DNA sequence of living bacterium. CAS-9 along with an accompanying RNA can also cut and remove few parts. Scientists have found a way to make CAS-9 programmable and costs of gene editing have come done significantly.

Video explaining CRISPR and CAS-9.

What lies ahead using programmable CAS-9 technology is not clearly known, things like removing cancer causing mutations and cure for genetic disorders are being actively discussed. Also designer babies could soon become reality. All of this has nothing to do with Phage therapy, since we are talking about phages I couldn’t resist myself sharing this brilliant innovation.

Finally in our losing battle with antibiotic resistance, phage therapy seems to be a promising alternative. Will it become a big thing or not, only time will tell.