MUMBAI: For more than a century, tuberculosis (TB) has held the world in its grip — a patient, persistent disease that outlives generations. Caused by the bacteria Mycobacterium tuberculosis, it defies time and medicine alike. Despite antibiotics, despite vaccines, despite decades of public health campaigns, the numbers refuse to fall where we want them to. In 2023 alone, an estimated 10.8 million people fell ill and 1.25 million died. India, burdened more heavily than any other nation, reported over 2.6 million cases in 2024. In plain terms — TB hasn’t gone anywhere. It continues to thrive, and scientists are still trying to answer the uncomfortable question: why?Part of the answer lies in TB’s shapeshifting nature. Once inside the body, the bacteria can slip into a sleep-like phase — latent or dormant TB — a kind of biological hibernation. Here, they remain alive, yet still. Silent tenants. No cough, no fever, no sign. People carrying latent TB don’t spread the disease, and for years nothing happens. But the quiet doesn’t mean safety. All it takes is a weakened immune system — another illness, HIV, certain medications — and TB can wake up. This is where medicine struggles. Most antibiotics target bacteria that are active and dividing. Dormant ones, barely growing, dodge the blow. They sit through treatment, unbothered, and survive — a phenomenon known as antibiotic tolerance.A research team led by Prof. Shobhna Kapoor (Department of Chemistry, IIT Bombay) and Prof. Marie-Isabel Aguilar (Monash University) decided to probe this stubborn mystery. Why are dormant TB bacteria so unaffected by antibiotics? Their findings, now published in Chemical Science, reveal how TB endures even under treatment — and how dismantling this defence might make existing drugs far more potent.Earlier research hinted that the answer might lie not inside the bacterium, but around it — within the fortress-like membrane made of fats, or lipids. Prof. Kapoor’s team followed that clue. They analysed how bacterial membranes change as TB moves from an active phase into dormancy, and whether those alterations affect the ability of drugs to get in.Working with live TB bacteria would be hazardous, so they turned to its gentler cousin — Mycobacterium smegmatis. Close enough to mimic TB behaviour, but safe for laboratory handling. They cultivated the bacteria under two conditions: one actively dividing, the other mimicking a dormant, slow-growing state.Then came the drugs — four familiar TB warriors: rifabutin, moxifloxacin, amikacin, and clarithromycin. The results were unmissable. Dormant bacteria required two to ten times more drug concentration for the same effect. As Prof. Kapoor puts it, “the same drug that worked well in the early stage of the disease would now be needed at a much higher concentration to kill the dormant/persistent TB cells. This change was not caused by genetic mutations, which usually explain antibiotic resistance.” The strain used showed no resistance-linked mutations. Something else was at play — likely the membrane itself.To understand what changed between the two states, the team mapped the membrane like a molecular census using advanced mass spectrometry. They identified over 270 lipids. Active bacteria brimmed with glycerophospholipids and glycolipids; dormant cells, meanwhile, were thick-skinned — packed with fatty acyls, wax-like and defensive. Lead author Ms. Anjana Menon, PhD scholar at the IITB-Monash Research Academy, explains, “We found clear differences between the lipid profiles of active and dormant cells.”The physical outcome was striking. Using fluorescence-based techniques, the researchers measured membrane fluidity — how tightly the lipids were packed. Active membranes were loose, fluid. Dormant ones felt like armour — rigid and ordered. Even cardiolipin, a lipid that keeps membranes flexible, dipped dramatically. “Cardiolipin helps keep the membrane slightly loose. When its level falls, the membrane becomes tighter and less permeable,” Ms. Menon notes.The team then tracked rifabutin’s journey. It slipped easily into active cells, but stopped at the door of dormant ones. “The rigid outer layer becomes the main barrier. It is the bacterium’s first and strongest line of defence,” says Prof. Kapoor.If the wall is the problem, weakening it might be the key. Instead of crafting brand-new antibiotics, the team suggests boosting old ones. “Even old drugs can work better if combined with a molecule that loosens the outer membrane,” says Prof. Kapoor. Enter antimicrobial peptides — small proteins that gently pry open membranes. They don’t kill bacteria alone, but paired with antibiotics, they help drugs seep through. “These peptides alone don’t kill the bacteria, but when combined with antibiotics, they help the drugs enter and act more effectively,” Prof. Kapoor adds.The next step is to repeat the study with real TB bacteria under high-security lab conditions. “Our lipid analysis is very detailed. It can easily be applied in labs that work with the actual TB strain,” shares Ms. Menon. If successful, this could shorten treatment, improve outcomes, and chip away at a disease that has refused to leave for a hundred years.
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