Tuberculosis (TB) is a treatable disease, but drug resistance is now a major public health concern exacerbated by the emergence of multi and extensively drug-resistant TB. India has the highest burden of Multi-Drug Resistant-TB (MDR-TB) bacteria with the World Health Organisation (WHO) putting the figure at 0.39 million cases worldwide and highlighting the need to stop its spread.
If long treatment, higher drug toxicity, and costly drug treatment make the MDR and extensively drug-resistant (XDR) TB challenging to treat, a group of scientists led by CSIR-Centre for Cellular & Molecular Biology (CCMB) director Vinay Kumar Nandicoori has, in a new study, established that mutations in DNA repair genes could be used for the early diagnosis of MDR/XDR-TB.
The study authored National Institute of Immunology (NII)‘s Saba Naz and University of Delhi’s CGMCP - Centre for Genetic Manipulation of Crop Plants, Paritiosh Kumar and researchers from other institutes had for the first time identified a ‘compromised DNA repair’ as one of the novel mechanisms for the evolution of drug resistance in Mycobacterium Tuberculosis (Mtb) which causes Tuberculosis (TB) in humans.
MDR-TB bacteria are resistant to first-line anti-TB drugs like Isoniazid and Rifampicin and extensively drug-resistant (XDR) when it becomes resistant to first-line TB drugs, any fluoroquinolones, and at least one additional Group A drug (Moxifloxacin, Levofloxacin, Linezolid, and Bedaquiline).
The rod-shaped Mtb enters the lungs through the respiratory route. While usually, the body can fight against it, in an immune-compromised state, it succumbs to bacterial infection as the bacteria keep replicating inside the lungs and eventually cause several lesions like ‘granuloma,’ a hallmark of TB. After a period, the granuloma bursts open, and bacteria enter the sputum, causing active disease, said the scientists.
Since the evolution of drug resistance in the Indian population has not been studied, scientists started analysing the genome sequence of bacteria isolated from TB patients from other parts of the world to understand the unknown mechanisms and bridge the gap between early diagnosis and treatment of MDR-TB.
Genome sequence data of the bacterial strains isolated from patients in other countries like Malawi, Russia, China, Estonia, the United Kingdom, Uganda, and the Netherlands were used.
“Using bioinformatics, we have analysed the genomic DNA of approximately 2,800 clinical strains and performed association analysis using drug-susceptible and drug-resistant bacteria. We identified that DNA repair, a process that guards the genome of bacteria, was found to be perturbed exclusively in the MDR/XDR strains,” said Dr. Nandicoori, in an exclusive interaction.
With the help of in vitro, in vivo, and ex vivo evolution experiments and whole genome sequencing of bacteria, it was successfully shown that perturbed DNA repair aids in the acquisition of drug resistance in Mtb, he explained.
Dr. Saba Naz, the primary author of the manuscript, said early detection would help clinicians to develop better drug regimens to thwart the progression of MDR/XDR-TB in the population. It would not only help decrease the burden of MDR/XDR in the infected population but also help decrease the spread of drug-resistant TB.
Other scientists in the research are Priyadarshini Sanyal, Sidra Khan, Yogendra Singh, and Umesh Varshney, and participating institutes being University of Delhi’s Department of Zoology and Indian Institute of Science (IISc) Bengaluru’s Department of Microbiology and Cell Biology. The study was published in eLIFE, a biomedical and life sciences scientific journal recently.