India could have a drug-resistance cure

IIT-Kanpur & CDRI scientists have developed a new molecule based on the fundamentals of how antibiotics attack bacteria

drug resistance cure, bacterial enzyme, NDLM1, CDRI, World Health Organization, antibiotics, global health emergency
India reports the largest total and per capita direct consumption of units of antibiotics globally.

It was a bacterial enzyme that unfairly dumped global infamy on India—the New Delhi metallo-beta-lactamase-1 (NDLM-1)—since it made bacteria resistant to carbapenems, a class of antibiotics that is the bulwark of treatment of antibiotic-resistant infections. Few “rise of the superbugs” stories in the media and in research journals would miss a mention of NDLM-1. Now, it is a bacterial enzyme that is at the heart of research by Indian scientists that promises to add crucial firepower to the anti-resistance fight. A study by researchers from the Indian Institute of Technology, Kanpur (IIT-K), and the Central Drug Research Institute (CDRI) has made a breakthrough in combatting antibiotic resistance in Staphylococcus aureus, a common bacteria that has become resistant to most drugs over the years. Resistance to what were, till recently, last-resort antibiotics makes the innocuous S.aureus lethal for many with low immunity.

The IIT-K-CDRI study research is based on a fundamental of how antibiotics attack bacteria. Most drugs in the market inhibit the function of subunit-A of gyrase, an enzyme that is essential for transcription of bacterial genetic matter, and, by extension, bacterial multiplication. But, antibiotic resistance has developed, thanks to bacteria evolving in a manner that the gyrase-A gets modified and drugs fail to bind to it. The IIT-K-CDRI study has come up with a new molecule that targets the subunit B of bacterial gyrase, and, thus, a new molecular framework that also allows existing antibiotics to act when used in combination with the new molecule. Now, gyrase-B doesn’t exhibit mutation as commonly as gyrase-A since the ATP (adenosine triphosphate)-binding site within gyrase-B, crucial to transcription, is highly conserved in bacteria. While gyrase-A is targeted by quinolones, the first-line of antibiotics, gyrase-B is targeted primarily by aminocoumarins and cyclothialidines, but there is no clinically available gyrase-B inhibiting drug. Now, mutations that confer resistance against all three antibiotic groups are known. The mutations that confer resistance to aminocourmarin and cyclothialidine are at the periphery of the ATP-binding site of gyrase-B. Which is why, the next generation of antibiotics need to target the ATP binding site of gyrase-B, given these will then be restricted to the portion of the enzyme that is conserved. The IIT-K-CDRI molecule does this, and when it is used in combination with fluoroquinolones, the latter inhibit gyrase-A—the new design has been found to be effective against bacteria in in vitro conditions.

The World Health Organization has flagged antimicrobial resistance as a global health emergency—by 2050, projections are, 10 million will die from superbugs, or anti-microbial resistance, beating even cancer deaths. India reports the largest total and per capita direct consumption of units of antibiotics globally. Abuse is rampant, too. Even as India already reports the fourth highest farm-consumption of antibiotics, and this is set to double by 2030, a study found that two-thirds of the poultry farms in Punjab used antibiotics—sub-therapeutic (low doses) use helps the birds gain weight faster—and were therefore thrice as likely as farms that were not using antibiotics to report multi-drug resistance (MDR). Part of antibiotic abuse in India stems from very poor awareness—a WHO multi-country survey a few years back found that 75% of the Indian respondents thought, incorrectly, that colds and flu can be treated with antibiotics and only 58% knew that they must complete the prescribed antibiotic course. The problem is made worse by the fact that the antibiotic-discovery pipeline has nearly run dry, though drug majors have shown some interest over the last few years. Well-meaning government initiatives to create awareness have achieved little, the on-ground abuse of antibiotics shows. Against such a backdrop, while the IIT-K-CDRI discovery is a major step forward, there needs to be ever-present acknowledgment of the fact that sustained efficacy of the new molecular framework faces age-old threats, unless antibiotic abuse is curbed meaningfully.

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