Antibiotics remain essential for treating a wide range of infections, including pneumonia, tuberculosis, urinary tract infections, and bloodstream infections. Doctors also rely on them to prevent infections during surgeries, organ transplants, and chemotherapy.
However, the widespread and often indiscriminate use of antibiotics has accelerated a global health crisis—antimicrobial resistance (AMR). According to a World Health Organization (WHO) report, in 2023 alone, one in six clinical laboratories worldwide confirmed bacterial infections resistant to antibiotic treatments.
As bacteria continue to evolve and evade existing drugs, researchers are now exploring innovative strategies to restore the effectiveness of existing antibiotics rather than solely developing new ones.
Scientists Explore a New Approach to Fight Resistance
Addressing this growing challenge, researchers from the Indian Institute of Technology (IIT) Bombay have developed a novel strategy to counter antibiotic resistance. The research team, led by Prof. Ruchi Anand and Prof. P. I. Pradeepkumar from the Department of Chemistry, focused on protecting existing antibiotics instead of creating new drugs.
Their findings, published in two complementary research papers, demonstrate how short DNA sequences known as aptamers can block bacterial enzymes responsible for antibiotic resistance. By preventing these enzymes from disabling antibiotics, the researchers were able to restore the effectiveness of commonly used drugs against resistant bacteria.
Prof. Ruchi Anand explained:
“Given the long, expensive path from drug discovery to clinic, improving existing drugs may be a more practical route. We know their safety and effects over the years and can use existing resources.”
How Bacteria Develop Resistance to Antibiotics
Many widely used antibiotics, including erythromycin and related drugs, work by binding to the bacterial ribosome, a molecular machine responsible for protein production. Once the antibiotic attaches to the ribosome, protein synthesis stops, and the bacteria die.
However, bacteria have developed sophisticated mechanisms to evade these drugs. One key strategy involves enzymes called erythromycin resistance methyltransferases (Erm proteins).
These enzymes add a methyl group to a specific site on ribosomal RNA, a process known as methylation. As a result, the antibiotic’s binding site subtly changes, preventing the drug from attaching effectively. Consequently, protein production continues and the bacteria survive, rendering the antibiotic ineffective.
DNA Aptamers Identified as Potential Resistance Blockers
In the first study, researchers Leena Badgujar, Damini Sahu, Prof. Ruchi Anand, and Prof. P. I. Pradeepkumar focused on DNA aptamers, which are short synthetic nucleic acid sequences capable of binding specific molecular targets.
Unlike traditional drugs, aptamers are relatively stable, synthetically produced, and easier to modify, making them promising candidates for therapeutic applications.
To identify aptamers capable of binding to a resistance enzyme called Erm42, the researchers used a laboratory technique known as SELEX (Systematic Evolution of Ligands by Exponential Enrichment). This method allows scientists to screen millions of DNA sequences and isolate those that bind strongly to a specific target.
After several rounds of selection and testing using gel-monitoring assays and surface plasmon resonance, the team successfully identified two aptamers that tightly bind to the Erm42 enzyme.
Aptamers Successfully Block Resistance Enzyme Activity
Binding to the enzyme alone was not sufficient; the aptamers also needed to block the enzyme’s function.
To test this, the researchers conducted biochemical experiments, including in vitro methylation assays, which measure how efficiently the enzyme performs its chemical function outside the cell.
As per the IIT Bombay press release, the results showed that the identified aptamers prevented the enzyme from transferring methyl groups to ribosomal RNA, effectively inhibiting Erm42 methyltransferase activity.
Prof. Pradeepkumar added that the team further refined the aptamers to improve performance:
“We reengineered the DNA aptamers by removing unneeded sequences to enhance their specificity towards the target protein.”
Liposome Delivery System Enhances Aptamer Effectiveness
Although the DNA aptamers performed well in laboratory tests, another challenge remained. Free DNA molecules are vulnerable to degradation by nucleases and often struggle to cross bacterial membranes, limiting their effectiveness inside bacterial cells.
To overcome this limitation, the researchers developed a liposome-based delivery system in their second study.
Liposomes are tiny spherical structures made of lipid bilayers, similar to natural cell membranes. In this study, each liposome contained a carefully designed mixture of three types of lipids:
- A positively charged lipid to attract negatively charged DNA
- A fusion-promoting lipid to help the particle merge with bacterial membranes
- A stabilising lipid to enhance durability in biological environments
The DNA aptamers were encapsulated inside these lipid particles, which measured 100–200 nanometres in diameter—an ideal size for cellular uptake.
Improved Uptake in Antibiotic-Resistant Bacteria
The researchers tested whether these aptamer-loaded liposomes could deliver DNA molecules into antibiotic-resistant Staphylococcus aureus, a common pathogen responsible for difficult-to-treat infections.
The results were striking. When delivered through liposomes, more than 90% of bacteria successfully absorbed the aptamers, compared with almost no uptake when the aptamers were delivered alone.
Furthermore, when the researchers tested the system against resistant bacterial cultures, liposome-delivered aptamers caused significantly higher bacterial death rates compared with antibiotics alone.
Prof. Ruchi Anand explained the significance of these findings:
“This is significant because we are inhibiting Erm activity. Methylation of the ribosome is not happening, and the drug can bind back again. The resistance has been reversed.”
Potential for Future Clinical Applications
Although the findings show strong promise, researchers emphasise that several factors must be evaluated before clinical use.
Prof. Pradeepkumar noted that the aptamers must avoid unintended interactions with proteins in the human body, while the liposome delivery system must be proven safe for human cells.
Nevertheless, Prof. Ruchi Anand remains optimistic about the approach. She highlighted that DNA synthesis is relatively straightforward, and liposome-based drug delivery systems are already widely used in modern medicine.
Moreover, scientists can further improve stability by applying chemical modifications at the ends of DNA molecules, a common strategy in nucleic acid therapeutics.
A New Strategy to Revive Existing Antibiotics
If successfully developed for therapeutic use, the engineered aptamers could be administered alongside existing antibiotics. By blocking bacterial resistance mechanisms, these molecules could restore the effectiveness of older antibiotics that bacteria have learned to evade.
Although additional research—including animal studies and pharmacokinetic analysis—is required, the concept represents a promising new direction in the fight against antimicrobial resistance.
As Prof. Ruchi Anand concluded:
“The beauty of the approach lies in the fact that we can resensitise old antibiotics.”