Research identifies new mechanisms to detect and weaken TB bacteria

Tuberculosis is often discussed in terms of infection and disease burden. But at the microscopic level, Mycobacterium tuberculosis (Mtb) is not just a pathogen, it is also a highly adaptive system that actively reshapes its environment and tightly regulates its own survival.

Emerging research highlights how this bacterium persists for years inside the human body by both manipulating host cells and fine-tuning its internal signalling systems.

Shifting outer shield

A key reason Mtb is so difficult to eliminate lies in its outer membrane which is a lipid-rich, dynamic structure that enables survival under stress.

Research led by Shobhna Kapoor, Indian Institute of Technology Bombay, shows that this membrane is not static. Instead, it continuously adapts as the bacterium shifts between active and dormant states.

These lipid changes are not just structural they help the bacterium evade immune detection and even resist antibiotics. “Our and others’ latest findings show that mycobacteria modulate their lipidome to vary the abundance of specific lipids, which harbour properties to evade immune recognition and hence go undetected,” Dr. Kapoor explains. “These lipids, further rigidify the cell wall, rendering the bacteria unresponsive to antibiotic treatment and hence able to persist within a human body for decades.”

Detecting what usually stays hidden

One of the major challenges in TB control is identifying infections that remain latent or undetected.

Dr. Kapoor’s team has developed a label-free, liquid crystal-based detection method that can distinguish between active and dormant bacterial states based on subtle lipid changes. Unlike conventional diagnostics, this approach does not rely on expensive reagents or complex infrastructure.

“This provides a proof of concept that liquid crystal platforms can differentiate between active and latent bacterial species,” she says. “The readout is simple and capturable by even smartphones.”

In high-burden settings like India where access, cost, and patient compliance remain barriers such low-cost, scalable diagnostics could be significant. Current methods like sputum testing and culture are often slower, while advanced immunological tests can be expensive and resource-intensive.

Beyond evasion, Mtb actively prepares host cells for infection. Dr. Kapoor’s work shows that bacterial lipids such as Sulfoglycolipid-1 can reorganise the host cell membrane and cytoskeleton (actin), making it easier for the bacterium to enter and survive.

“It is becoming clear that lipid molecules of mycobacteria play active roles in infection,” she notes. These lipids can “remodel the human cell membrane, leading to higher bacterial uptake and survival by altering inflammatory responses.” In simpler terms, the bacterium does not just invade, it conditions the host cell to accept it.

Controlled system inside bacterium

Another line of research focuses on how Mtb regulates itself. At JIS Institute of Advanced Studies and Research, Kamakshi Sureka Paul and her team study cyclic-di-AMP (c-di-AMP), a small but critical signalling molecule inside the bacterium. This molecule governs essential processes such as growth, metabolism, stress response, and virulence. Their research shows that the enzymes controlling c-di-AMP are highly conserved across mycobacterial species, hightlighting how important precise regulation is for survival.

The group has also developed a FRET-based biosensor– a molecular tool that uses Förster Resonance Energy Transfer (FRET) to detect, quantify, and visualise biological molecules or interactions in real-time that allows real-time monitoring of this molecule inside living cells , a shift from traditional methods that only provide static snapshots.

New direction for drug-resistant TB

The promising implication of this work lies perhaps lies in treatment. Instead of directly killing the bacterium which often drives antibiotic resistance researchers are now exploring ways to disrupt its internal signalling systems.“Targeting bacterial intracellular signalling pathways represents a promising strategy for combating drug-resistant tuberculosis,” Dr. Paul explains. “This approach does not directly kill the bacteria but instead weakens them, making them more susceptible to existing antibiotics.”

Because this method reduces selective pressure, it may slow the emergence of drug-resistant strains one of the biggest challenges in TB control today.

The findings also shed light on how Mtb engages with the body’s immune defences.“One mechanism is through activation of the innate immune response via the cGAS–STING pathway,” says Dr. Paul, referring to a key immune signalling route triggered by bacterial molecules. At the same time, Dr. Kapoor’s work highlights how bacterial lipids manipulate immune responses at the cellular level, showing that host–pathogen interaction is not a single pathway, but a layered and dynamic process.

Addressing the gaps

Despite these advances, a gap remains between laboratory findings and patient outcomes.

Much of Dr. Kapoor’s work relies on Mycobacterium smegmatis, a model organism used in place of Mtb due to biosafety constraints. “The findings are best hypotheses unless tested within real-life samples,” she notes, pointing to the need for stronger collaboration with clinical settings.

Still, translation efforts are underway. Dr. Kapoor is also associated with work involving Lionex India Biotech Private Limited in collaboration with Lionex GmbH to develop diagnostic tools for active TB.

Thes studies show that Mtb’s resilience is not driven by a single factor. It is the result of interconnected systems lipid-based defence, host manipulation, and precise internal signalling that allow the bacterium to sense, adapt, and endure.

The findings can contribute to shift the direction of TB research, from simply killing the bacterium to outmanoeuvring it, detecting it earlier, weakening its defences, and disrupting the systems that keep it alive.

Published – March 24, 2026 09:39 am IST