Comparative genome analysis of two super-extensive drug-resistant isolates of Mycobacterium tuberculosis

[Objective] Based on the genome sequences of two super extensive drug resistant isolates of Mycobacterium tuberculosis, we attempted to identify the lineage-specific SNPs and found the drug resistant-associated mutations in them. [Methods] By using the next-generation sequencing technology on two super-extensive drug resistant isolates of mycobacterium tuberculosis(FJ05194 and GuangZ0019), we compared them with the reference sequence to identify the single nucleotide polymorphisms(SNP) and divided the SNPs into lineage-specific and isolate-specific SNPs. Check the coordinate of SNPs on the genome, then we did the enrichment analysis of the lineage-specific SNPs, and were able to found out the drug resistant mutations from the isolate-specific SNPs by overlapping with the candidate drug resistance associated regions. [Results] The Lineage2-specific SNPs was significantly enriched on ABC transpoters and nucleotide excision repair KEGG pathways, and the extensive drug resistance were mainly attributed to the mutation of the well-known genes(rpoB, katG, rpsl, gyrA, gyrB, embB, ethA and so on), but the capreomycin and kanamycin resistance was probably due to some candidate resistant-associated genes(Rv1393c, Rv0265c, narX) and the efflux pump genes(pstB, Rv2333c and Rv2687c). [Conclusion] The Lineage2-specific-SNPs possible result in the high mutation rate and drug resistance of the Lineage2. And the mechanism of super extensive drug resistance is more complex, it not only involve with the drug target and drug activation genes, but also some unclear candidate genes such as compensatory genes and efflux pump genes.