Drug resistance and persistence in Mycobacterium tuberculosis
As we’ve discussed before, Mycobacterium tuberculosis is the major cause of tuberculosis, a disease that has plagued humans for millennia. The oldest recorded case of TB is in a 500 000-year-old fossil of Homo erectus. Despite the best efforts of modern medicine, we have so far failed in our fight against this disease, which kills up to two million people every year.
The problem is that M. tuberculosis infections are both hard to detect and hard to treat. Mycobacteria have a waxy coating of fats called mycolic acids that make them naturally resistant to many antibiotics and helps them hide inside human immune cells. Because the immune system can’t attack itself, this is a pretty ingenious hiding place. It typically takes six months of multidrug therapy to cure an active TB infection and nine months to kill a latent infection (that is, the TB cells that are hiding). Some of the cells that are hiding are known as ‘persisters’, and it’s these cells that take longer to kill in a latent infection.
In a recent study, scientists developed a new way to study persister cells in the lab. They found that in a large collection (or population) of TB cells, a small number form a distinct subgroup of persisters. Weirdly, despite all the cells being genetically identical, the persisters are more resistant to antibiotics than all the other normal TB cells.
However, the persisters are only resistant to antibiotics if the oxygen supply is as low as it is inside a human immune cell. We already know that antibiotics result in the formation of reactive oxygen species (ROS) – free radicals that whizz about like bullets, smashing into important molecules like DNA and killing the cell from the inside. In low oxygen, antibiotics form less ROS, and this probably explains why these cells can survive.
This chink in their armour should allow new treatments to be developed: the addition of an antibiotic called clofazimine, which generates very high levels of ROS, eradicated the persister cells. Combining drugs that generate high levels of ROS along with the normal cocktail of antibiotics used to treat TB should provide us with new weapons to tackle this devastating disease.
Grant SS, Kaufmann BB, Chand NS, Haseley N, & Hung DT (2012). Eradication of bacterial persisters with antibiotic-generated hydroxyl radicals. Proceedings of the National Academy of Sciences of the United States of America, 109 (30), 12147-52 PMID: 22778419