IITGN-Led Team Designs Molecule That Attacks MRSA Through an Untapped Enzyme

Nearly a century after a stray mold accidentally destroyed a colony of Staphylococcus aureus (S. aureus) in Alexander Fleming's London laboratory in 1928, leading to the discovery of penicillin, the same bacterium is now one of the World Health Organization's most-feared superbugs. Methicillin-resistant S. aureus, or MRSA, is the "S" in ESKAPE, a group of six pathogens notorious for evading multiple antibiotics, and it causes skin, bloodstream and surgical-implant infections.

A 2024 Global Research on Antimicrobial Resistance study published in The Lancet estimated that drug-resistant infections could directly kill more than 39 million people between 2025 and 2050, with resistant Staphylococcus infections directly linked to about 130,000 deaths. South Asia, including India, is expected to bear the heaviest burden, at an estimated 11.8 million deaths.

Against that backdrop, a collaborative study involving the Indian Institute of Technology Gandhinagar (IITGN) has designed a laboratory-made molecule that kills S. aureus by disabling an enzyme most antibiotics ignore, called thymidine kinase, which helps the bacterium recycle the chemical building blocks it needs to copy and repair its DNA. "Most antibiotics attack bacteria through a handful of familiar routes, including puncturing their walls and jamming their protein-making machinery. The trouble is that bacteria have spent decades learning to dodge those blows," said Professor Bhaskar Datta of IITGN's Departments of Chemistry and Biological Sciences and Engineering, the study's corresponding author. The study, published in the journal Chemistry Biodiversity, also involved researchers from Jamia Millia Islamia, Jamia Hamdard, Xi'an Jiaotong-Liverpool University and the Ahmedabad-based company Sushen Medicamentos.

Working from a crystal structure of S. aureus thymidine kinase recently solved by Md. Imtaiyaz Hassan's team at Jamia Millia Islamia, the chemists assembled a new molecule from a thiazole ring and a sulfonamide group, a chemical descendant of the earliest antibiotics. From nine synthesized candidates, one compound, called DSA3, showed the strongest predicted interaction with thymidine kinase's ATP-binding pocket, the site where the enzyme normally grabs its chemical fuel.

Laboratory experiments confirmed that DSA3 binds to thymidine kinase and reduces its activity, with a concentration of 6.996 micromolar cutting the enzyme's activity in half. Fluorescence measurements and a separate heat-based technique called isothermal titration calorimetry both provided further evidence that DSA3 forms a stable interaction with the enzyme.