Researchers at the Indian Institute of Technology (IIT) Bombay have uncovered how Mycobacterium tuberculosis — the bacterium responsible for Tuberculosis (TB) — manages to survive antibiotic treatment by altering the structure of its outer fatty layer. TB remains the world’s most infectious and deadly bacterial disease, and despite effective drugs and large-scale vaccination efforts, it continues to claim lives globally.
In 2024 alone, an estimated 10.7 million people developed TB, and 1.23 million died from it. India continues to bear one of the heaviest burdens, recording more than 2.71 million cases in the same year.
The study, published in the journal Chemical Science, highlights that the key to the bacterium’s drug tolerance lies in its membrane — a complex, protective barrier made mostly of lipids (fats). These lipids play a crucial role in shielding the bacteria and determining how well antibiotics can reach the internal parts of the cell.
To understand how TB bacteria evade treatment, the researchers grew M. tuberculosis under two different conditions:
An active, fast-growing phase, similar to what happens during active TB infection.
A dormant, slow-growing phase, mimicking latent TB, where the bacteria hide in the body for years.
When the team tested four commonly used TB antibiotics — rifabutin, moxifloxacin, amikacin, and clarithromycin — they discovered that dormant bacteria required two to ten times higher drug concentrations to stop their growth compared to active bacteria. Importantly, this reduced sensitivity was not due to genetic mutations, which are typically associated with antibiotic resistance. Instead, it was linked to physical changes in the bacteria’s outer membrane.
The researchers identified more than 270 different lipid molecules in the bacterial membrane. Active bacteria had loose, more fluid membranes, while dormant bacteria had rigid, tightly packed outer layers — a structural defence that made it much harder for drugs to penetrate.
Further investigation showed that rifabutin, a frontline TB drug, could easily enter active cells but struggled to pass through the tough outer membrane of dormant bacteria. This rigid membrane acts as a powerful shield, preventing antibiotics from reaching their targets.
The study suggests that weakening this outer membrane could significantly improve the effectiveness of existing TB drugs. According to the researchers, combining current antibiotics with compounds that loosen the outer lipid layer may restore drug sensitivity and enhance treatment outcomes — all without causing long-term resistance.
This one opens new pathways for developing combination therapies aimed at overcoming TB drug tolerance, especially in dormant infections that are often responsible for treatment failure and relapse.