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Mycobacterium tuberculosis whole genomes from North East India suggest the prevalence of fluoroquinolone resistance Beijing strains

Arup Ghosh1,3, Himadri Bhusan Bal2, Viplov Kumar Biswas1,3, Dasarathi Das2, Sunil Kumar Raghav1,3

1. Immunogenomics & Systems Biology Laboratory, Institute of Life Sciences, Bhubaneswar

2. National Reference Laboratory, Regional Medical Research Centre (ICMR), Bhubaneswar

3. School of Biotechnology, Kalinga Institute of Industrial Technology, Bhubaneswar

As per WHO 2019 tuberculosis report, 87% of all the new tuberculosis cases are reported from 30 high TB burden counties, and among them, eight countries account for two-thirds of total new cases. Currently, India reports the most number of new tuberculosis cases followed by Indonesia and China, also India is home to the second-highest occurrence of multidrug resistance cases. Although the genetic diversity of tuberculosis has been profiled using the whole-genome sequencing techniques in most of the developed nations, there is a very limited exploration in high TB burden countries like India. Recent publications suggest that two major lineages are dominant in southern and north India. But to date, the prevalent tuberculosis lineages in the North East and Eastern parts of India have not been profiled using next-generation sequencing technology. To bridge this gap we have sequenced 122 Mycobacterium tuberculosis isolates consisting of 66 samples from North-East India and 56 samples from Odisha collected by the National Reference Laboratory(NRL) Bhubaneswar, Odisha. We have also profiled the drug resistance profile of respective samples using phenotype DST using a culture-based method. We checked the drug resistance profile against rifampicin, fluoroquinolones, low and high concentrations of kanamycin, amikacin, capreomycin, and levofloxacin.  As most of the samples collected from North East were already known to be rifampicin-resistant (CBNAAT) we checked them for all the drugs, but except for one sample, all samples from Odisha were susceptible to first-line drugs. From the genomic data first, we checked for lineage diversity in the clinical isolates using computational prediction of spoligotypes. We observed the occurrence of twelve clades. The majority of the North East samples showed the presence of Beijing clade whereas samples from Odisha showed the presence of Central Asian Strain (CAS-Delhi) and East African Indian(EAI) sub-lineages. Stratification of drug resistance phenotypes showed co-occurrence of rifampicin and fluoroquinolones in North East India samples although the subjects have not received any prior treatments with such drugs. To understand the genetic basis of this resistance we called single nucleotide variants and observed a high density of non-synonymous variants in the rpoB, gyrA, and gyrB region. Our findings suggest that there is a need for region-specific diagnostic methods/tools for faster detection of drug resistance phenotypes to control the spread of multi-drug resistance tuberculosis in India.