At a time when researchers across the world are looking for ways to combat the steadily growing antimicrobial resistance — making infections difficult to treat and sometime deadly — IIT Bombay has come up with a novel solution. Instead of inventing new antibiotics, they have found a way to make the old ones work again.

There were an estimated 2.6 lakh deaths in India in 2021 directly attributable to antimicrobial resistance, according to data from the Global Burden of Diseases study. Meaning, these deaths could have been prevented had the infections responded to treatment.

So, what did the IIT-B researcher find? 

One of the most commonly used family of antibiotics called macrolides — which includes drugs such as azithromycin and erythromycin — target the bacteria’s protein making machine ribosome. Once these antibiotics stick to the ribosome, the bacteria cannot produce proteins it needs to live, and eventually dies.

The bacteria fight back using Erm enzymes to modify the ribosome in a way that the antibiotics cannot attach with it — akin to changing the lock to prevent the key from working. This helps the bacteria thrive even in the presence of the antibiotics.

IIT B researchers Leena Badgujar, Damini Sahu, Ruchi Anand, and Pradeepkumar PI found a way to prevent the bacteria from changing the locks. They used short, synthetic strands of DNA called aptamers to bind with the resistance causing Erm42 enzyme. They screened million of DNA sequences to choose two aptamers. “We reengineered the DNA aptamers by removing unneeded sequences to enhance their specificity towards the target protein,” says Professor Pradeepkumar.

When they tested it in the laboratory, the researchers found that these aptamers were effective in preventing the Erm enzyme from changing the lock.

But, they were faced with another challenge. How could they deliver these aptamers to the bacterial cells? These molecules are vulnerable to degradation and cannot cross bacterial membranes easily.

Another team led by Swagata Patra found the solution — a fat bubble. Liposomes are tiny, spherical, double-layered structures that are similar to all biological cell membranes, meaning it can encapsulate the aptamers and carry them inside the bacterial cell membranes. The liposomes were engineered by the team to bind with DNA for encapsulating the aptamers; to promote membrane fusion for entry; and to enhance stability.

And, did it work? 

The researchers tested the system on antibiotic-resistant Staphylococcus aureus, a major cause of difficult-to-treat infections.

They found that uptake of aptamers exceeded 90% when delivered via liposomes, compared to negligible uptake without them. And, the combination of aptamers and antibiotics led to significantly higher bacterial cell death than antibiotics alone.  “This is significant because we are inhibiting Erm activity and the drug can bind again with the ribosomes. The resistance has been reversed,” Professor Anand said.

Why is this significant? 

While this is an early proof-of concept, it marks a shift in how scientists approach antimicrobial resistance. Instead of developing stronger antibiotics — or ones that use completely different mechanisms — the researchers have found a way to disable resistance mechanisms, making older antibiotics effective again.

This method has several advantages: it extends the lifespan of existing antibiotics, reduces the need for new drugs, and builds on technologies already used in medicine. “Synthesising DNA is relatively straightforward, and liposome formulations are already widely used in medicine. Stability of aptamers can be further improved by chemical modifications —strategies routinely used in nucleic acid therapeutics,” Professor Anand said.

And, it can be a life-saver. Developing new antibiotics is a long, arduous, expensive and uncertain process. It can take over a decade for a drug to move from discovery to clinical use. Even when new antibiotics are introduced, bacteria often evolve resistance quickly.

Between 2017 and 2022, only about a dozen new antibiotics entered the market, most of them derivatives of existing drug classes—making them vulnerable to already evolved or new resistance mechanisms, the researchers said.

This has pushed scientists to explore alternative strategies—such as preserving and enhancing the effectiveness of existing drugs. “Given the long, expensive path from drug discovery to clinic, improving existing drugs may be a more practical route. We know its safety and effectiveness over the years,” said Professor Anand.