India is home to highest number of drug-resistant TB patients

Administering anti-malarial drug Chloroquine (CQ) with anti-TB drugs can reduce the tolerance of the TB bacteria, mycobacterium tuberculosis (Mtb), towards it. That, in turn, can help fight drug-resistant TB, according to a new research whose findings were published in Science Translational Medicine, a journal of American Association for the Advancement of Science.

The first-of-its-kind research was conducted on mice by scientists from the Indian Institute of Science in collaboration with the National Centre for Biological Science and Foundation for Neglected Disease Research.

If it translates into positive results for clinical trials on humans, it will be an important milestone for India. The country has the most number of TB and drug-resistant TB cases, according to the Global TB report 2019.

India contributed to as many as 27 per cent of the world’s drug-resistant TB cases, followed by China (14 per cent). That means India harbours 130,000 drug-resistant TB cases.

A challenge in TB treatment is that it takes six months or more as the bacteria persists in the body for long and strongly fights the drug. The drug thus takes long to kill the bacteria. The duration gives the bacteria enough time to diversify, mutate and produce sub-populations to become tolerant against the drug.

Proposed Regimen

“Tolerance comes when the bacteria affect human immune cells, like when it enters macrophages (white blood cells). So at IISC we have identified that bacteria that is tolerant is actually hiding in macrophages,” Amit Singh from IISc, lead resercher on the study, told Down To Earth.

“These particular macrophages have slightly more acidic pH than those sensitive to the drugs (those which get eliminated by the drugs). This acidity is signal for bacteria to launch an adaptation programme to tolerate oxidative stress of the drug,” he added.

If the acidic pH was not allowed in macrophages, one could interfere in the bacteria’s adaptation and the drug would remain sensitive, Singh said. This is what the scientists did.

“My group at the IISC has developed a biosensor to peek inside the bacterial subpopulations in real time,” he said. 

Offsetting acidic pH by the licensed anti-malarial drug Chloroquine restored homogeneity in the bacterial population — the diversification of bacterial population could be stopped — according to Singh.

“This significantly potentiated the activity of anti-TB drugs used in clinics, and reduced relapse rates as without an acidic pH environment the bacteria will not think about undergoing an adaptation programme. It remains sensitive to the drug,” he added.

Chloroquine successfully counteracted drug tolerance and relapse in mice, according to the research. Also, it exhibited no adverse interaction with anti-TB drugs. The excellent oral bioavailabity and few other factors, the researchers said, made it a good candidate for developing new therapeutic combinations for the treatment of TB.

Asked about TB patients without malarial infection, Singh said: “Chloroquine has a long history of safe usage in humans. Moreover, the concentrations used in our study is 10-20 fold lower than what is used to treat malaria.

“Further, a chronic form of Q fever caused by bacterium Coxiella burnetti in humans requires 18-24 months of Chloroquine in combination with doxycycline. Chloroquine is also used for the long-term treatment of rheumatoid arthritis (RA). Therefore, we don’t anticipate any major side effects of Chloroquine on TB patients.”

He, however, added that it needed in-depth experimentation, using human subjects.

Challenges too

Several issues remained before the therapy can be combined with standard anti-TB therapy, according to the paper.

CQ’s efficacy in shortening drug-resistant TB infections was yet to be evaluated.

The research was conducted in vivo only; human trials with the regimen may be a long way.

“Despite treatment with anti-TB drugs, Mtb cells persist in animal tissues and the sputum of patients with TB in a metabolically altered state and remain undetectable by viable counts. It will be interesting to investigate the impact of CQ on these heterogeneous subpopulations of Mtb that are difficult to detect and retain persister phenotypes in animal models,” the paper added.

Singh said eradicating drug-tolerant bacteria using Chloroquine was likely to inhibit the evolution of drug-resistant MDR/XDR strains of Mtb.

“This study provides a solid foundation to initiate human clinical trials to shorten antibiotic treatment of tuberculosis using Chloroquine in combinations with anti-TB drugs. If successful, Chloroquine combination can reduce the therapy time from six months to possibly four months or shorter,” he added.