Early sentinels of multidrug-resistant TB

Scanning electron micrograph of Mycobacterium tuberculosis, the bacteria that cause TB.NIAID

TB is a contagious disease caused by infection with Mycobacterium tuberculosis (Mtb) bacteria. It’s spread through the air and usually affects the lungs. TB is a leading cause of disability worldwide. It results in 1.5 million deaths each year. Of those, about 480,000 are caused by multidrug-resistant TB, which is resistant to at least 2 of the most potent TB drugs available: rifampicin and isoniazid. Treatment for multidrug-resistant TB has significant side effects and can last more than 18 months.

Effective TB treatment depends on detecting resistance as early as possible. The main diagnostic test for multidrug-resistant TB is called Xpert MTB/RIF. It detects Mtb strains resistant to rifampicin. Testing against rifampicin resistance is used as a “proxy” for identifying multidrug-resistant TB and assumes that resistance to both rifampicin and isoniazid is present, which then suggests that patients should be prescribed drug therapy specific for multidrug-resistant TB. However, recent studies have found that most strains evolve resistance to isoniazid before rifampicin. A team led by Dr. Ashlee M. Earl of the Broad Institute of MIT and Harvard set out to study the development of genetic mutations that lead to multidrug-resistant TB. These could serve as early sentinels to enable better tracking and treatments. The work was supported by NIH’s National Institute of Allergy and Infectious Diseases (NIAID). Results were published online in Nature Genetics on January 16, 2017.

The researchers examined whole-genome sequences from more than 5,300 Mtb strains isolated from TB patients from 48 countries on 5 continents. They found that more than 40% of the strains carried mutations previously implicated in drug resistance, and 18% carried mutations for both rifampicin and isoniazid resistance. Additionally, 5% carried mutations for resistance to 4 TB drugs—rifampicin, isoniazid, ofloxacin, and kanamycin—classifying them as “extensively” drug resistant Mtb.

The team’s analysis suggested that drug resistance arose through similar mechanisms in different geographic regions. In fact, they calculated that multi-drug resistant and extensively drug-resistant strains evolved independently in the sample hundreds of times. Notably, isoniazid resistance preceded resistance to rifampicin or other drugs in nearly all cases. These results suggest that by the time a mutation is detectable by the Xpert MTB/RIF test, the strain is likely already resistant to isoniazid and other drugs.

The scientists identified several genetic mutations that often arise before multidrug resistance. The most common by far caused isoniazid resistance and was in a gene called katG. The early identification and appropriate treatment of people with isoniazid-resistant Mtb strains might thus prevent the spread of strains resistant to additional drugs.

“These results suggest that a universal diagnostic test that includes harbinger mutations, such as the key katG mutation, could serve as an early warning signal for multidrug resistance,” Earl says. “Surveillance efforts that target these mutations could help health authorities better allocate resources to combat the emergence and spread of multidrug-resistant TB strains.”

Future studies will be needed to confirm that these harbinger mutations increase the risk of developing multidrug-resistant TB within a given population.

—by Harrison Wein, Ph.D.