Genomic signatures of drug resistance in highly resistant Mycobacterium tuberculosis strains of the early ancient sublineage of Beijing genotype in Russia

Abstract

The Mycobacterium tuberculosis Beijing genotype is a clinically and epidemiologically important lineage that is subdivided into ancient/ancestral and modern strains. In our previous study in western Siberia, we identified variable number of tandem repeats (VNTR)-based clusters within the early ancient sublineage of the Beijing genotype characterized by an unexpectedly high rate of extensive drug resistance (XDR). In the current study, next generation sequencing data were analysed to gain insight into genomic signatures underlying drug resistance of these strains. A total of 184 genomes of the Beijing early ancient sublineage from Russia (16), China (15), Japan (36), Korea (25), Vietnam (18), Thailand (73), and the USA (1) were used for phylogenetic analysis. The drug-resistant profile was deduced genotypically. The Russian isolates were distributed into two clusters and were all drug resistant, mainly pre-XDR and XDR. The largest of these clusters included only Russian isolates from remote locations in both Asian and European parts of the country. All its isolates had a quadruple drug resistance (to isoniazid, rifampin, ethambutol and streptomycin) due to the 6-mutation signature (KatG Ser315Thr, KatG Ile335Val, RpoB Ser450Leu, RpoC Asp485Asn, EmbB Gln497Arg, and RpsL Lys43Arg). In most samples, it was complemented with additional and different pncA, gyrA and rrs mutations leading to the pre-XDR/XDR genotype. Phylogenomic analysis indicates a distant origin of this Russian resistant cluster in the early 1970s but location and circumstances are yet to be clarified.