Innate immune proteins have been fighting infections in all living organisms for millions of years and bacteria have never been able to develop resistance against them. Despite this well-known fact, no one explored the possibility of leveraging this mechanism to counter one of the worst medical crises in modern times: antimicrobial resistance (AMR).
Now, for the first time, a team of Indian scientists has proved that these proteins can be exploited as antibacterial agents against antibiotic resistant bacteria. Scientists at the Department of Biophysics at All India Institute of Medical Sciences, New Delhi, have shown that the innate immune proteins from animals living in extreme climates and environments, such as a high degree of cold, heat or the most filthy conditions, have become more potent. These more potent proteins can be used as protein antibiotics to fight the infections of human body even against the strongest bugs, thereby eliminating the phenomenon called drug resistance. This is the latest from a scientist community that has been burning the midnight oil for the last several decades to develop new antibiotics to fight drug-resistant bacteria.
Prof TP Singh, a distinguished Fellow of Science and Engineering Research Board (SERB) and the former Head of the Biophysics Department at AIIMS-New Delhi, who led the path-breaking research, believes that evolving science will always find answers to even the most difficult challenges and there isn’t any reason to get panicky about AMR or to call this a return to the ‘pre-antibiotic era’. Prof. Singh, who has played an active role in the development of drug design in the fields of antibacterial therapeutics, tuberculosis, inflammation, cancer and gastropathy, shares his insights and experiences on this first-of-its-kind research with Editor C H Unnikrishnan.
Enhancing the potency of innate immune proteins to overcome AMR is a pathbreaking concept. Can you explain the mechanism and how advanced the project is?
As you know, innate immune proteins have been there in every living organism, including humans, for millions of years, and it has been instantly recognising and fighting infections the moment bacteria enter the body. Therefore, they (bacteria) never developed resistance in humans or in any other living things.
But, of late, antimicrobial resistance has become one of the key medical challenges in the world and existing antibiotics have become less effective in fighting infection as the bacteria have become stronger. While there are many factors — the abuse of antibiotics, consumption of food that helps the development of microbial resistance and the natural survival instinct of the bacteria and mutations — which have created this so-called superbug crisis, medical science has been exploring various strategies to counter this, including developing new antibiotics. The latest update is that the innate immune proteins have several modes of binding and multiple pathways. If we can exploit these principles and make proteins with the same modes of function, but of higher potency, we can make antibiotics that can completely eliminate the possibility of bacterial resistance.
So, we have now examined these proteins from extremophiles such as yaks that live in extremely cold climate, camels from hot deserts and porcines which inhabit the most unhygienic conditions. These animals have exposure to microorganisms that survive in even more difficult or tougher conditions. So, the innate immune proteins in these animals have been modified to become more potent to kill those stronger bacteria. We want to use the innate immune proteins from these animals as therapeutic molecules against infections in humans to fight the resistant bacteria, and this becomes an antibiotic without any resistance. This is the main concept behind this project.
The knowledge of innate immune proteins has been there for long.
Why was such a concept not explored earlier?
The knowledge has been there for long, but none thought of this concept or along these lines earlier because the structure of these proteins was not known or studied. In fact, ours (the team at AIIMS, New Delhi) is the first project in the world that has explored this possibility. We have studied the structure of these proteins and have seen certain modifications that have enhanced them to fight the bacteria from those extreme conditions. With this, what we have proved is that one can make more potent innate immune proteins by combining proteins from extremophiles such as yaks, camels and porcines together, and make therapeutic molecules to fight stronger bacteria. In other words, we can develop resistance-free antibiotics.
At what stage is the project now and how are you going to translate the outcome into practical therapeutic use?
The concept has already been proven in the laboratory with a high level of clarity and we will soon go for animal studies and then trials in humans. Since protein structures are not very different in humans and animals, it would require only small modifications or a few mutations to prepare these for human use for therapeutic applications. This way, these more and multi-potent proteins can be primarily injected into humans as antibiotics that are resistance-free against all groups of microbes. We have already studied camel and porcine proteins and are currently applying the same learnings to yaks.
We have also experimented on the acceptance levels of camel and porcine proteins in humans. We need to validate the same using proteins from yak. These three animals have innate immune proteins which survive in the respective conditions and which are modified differently to enhance their potency to fight bacteria —. These proteins can also be combined for further enhancement covering all three conditions for therapeutic application. In fact, we have also seen protein structures from other species like sheep, goat etc..
As we have already established that these are better and more effective, we will soon go for animal trials and then a clinical study in humans by collaborating with some companies at the next stage of development.
Given that innate immune proteins are the first line of defence in the body against infection, this line of research to develop new antibiotics is important. Also, these proteins typically bind to the cell walls of the bacteria and can fight against any infection, including gram-negative and gram-positive.
Even as the scientific community comes up with such new breakthroughs, the drug industry is often not interested to take them forward to finally bring them into the market. Why is there this contradiction?
There are multiple reasons for this. The problems faced by the industry in developing drugs for infections include geographical variations of diseases, the effort and risks involved in the development process, heavy investment and low profitability. Infective diseases typically vary from region to region. So the markets that these companies can target with these products are not common. Therefore achieving bigger volumes is often not possible. Moreover, product development is not easy because microbials, in general, have a tendency to modify their sites frequently. Considering these challenges, the profitability of the anti-infection business may not always match the investment required. Thus, the industry is typically reluctant to focus on antibiotics. That’s the reason why we haven’t seen many new antibiotics entering the market of late. But, at the same time, technologies involving path-breaking discoveries and wider applicability can certainly attract increased industry interest.