A team from Rockefeller University and three other US institutions have found the enzyme which they believe allows the bug to prove so persistent.
Currently, patients diagnosed with TB usually end up taking a combination of drugs for at least six months to achieve a cure.
This makes it more likely that patients will drop out without completing the course, both harming their prospects, and increasing the chances that the strain they carry will acquire more drug resistance.
Although the body's immune system attacks the invading bacteria, it is unable to completely wipe them out.
This is because the bacteria can remain in a "latent" phase, evading destruction by the immune system, but able to flare again into full-blown infection should the immune system become weakened for any reason.
Key chemical
The scientists say they have found a key chemical produced by the M. tuberculosis bacterium which allows it to survive in this latent phase.
This enzyme, called isocitrate lyase (ICL), means the bacterium can draw energy from chemicals found abundantly in cells.
The scientists believe that a drug which targeted the gene for ICL would stop the TB hiding so effectively.
Lead researcher, John McKinney, said: "A drug that inhibits ICL activity or synthesis might allow us to shorten the duration of chemotherapy from six months or more to just a few weeks.
"This would have an enormous impact on patient compliance and cure rates."
The researchers proved their theories about ICL by creating a mutant strain of the bug which lacked the relevant gene.
Mice infected with this were compared to mice infected with normal TB.
During the early stages, progress of the infection was identical - however, later on, the ICL-lacking bacteria were largely cleared by the immune system.
The report was published in the Journal Nature.