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. 2010 Nov 26:11:670.
doi: 10.1186/1471-2164-11-670.

The non-clonality of drug resistance in Beijing-genotype isolates of Mycobacterium tuberculosis from the Western Cape of South Africa

Thomas R Ioerger  1 , Yicheng Feng, Xiaohua Chen, Karen M Dobos, Thomas C Victor, Elizabeth M Streicher, Robin M Warren, Nicolaas C Gey van Pittius, Paul D Van Helden, James C Sacchettini
Affiliations

The non-clonality of drug resistance in Beijing-genotype isolates of Mycobacterium tuberculosis from the Western Cape of South Africa

Thomas R Ioerger et al. BMC Genomics. .

Abstract

Background: The Beijing genotype of M. tuberculosis is a virulent strain that is disseminating worldwide and has a strong association with drug resistance. In the Western Cape of South Africa, epidemiological studies have identified the R220 cluster of the Beijing genotype as a major contributor to a recent outbreak of drug-resistant tuberculosis. Although the outbreak is considered to be due to clonal transmission, the relationship among drug resistant isolates has not yet been established.

Results: To better understand the evolution of drug resistance among these strains, 14 drug-resistant clinical isolates of the Beijing genotype were sequenced by whole-genome sequencing, including eight from R220 and six from a more ancestral Beijing cluster, R86, for comparison. While each cluster shares a distinct resistance mutation for isoniazid, mapping of other drug-resistance mutations onto a phylogenetic tree constructed from single nucleotide polymorphisms shows that resistance mutations to many drugs have arisen multiple times independently within each cluster of isolates. Thus, drug resistance among these isolates appears to be acquired, not clonally derived. This observation suggests that, although the Beijing genotype as a whole might have selective advantages enabling its rapid dissemination, the XDR isolates are relatively less fit and do not propagate well. Although it has been hypothesized that the increased frequency of drug resistance in some Beijing lineages might be caused by a mutator phenotype, no significant shift in synonymous substitution patterns is observed in the genomes.

Conclusion: While MDR-TB is spreading by transmission in the Western Cape, our data suggests that further drug resistance (i.e. XDR-TB) at this stage is acquired.

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Figures

Figure 1
Figure 1
IS6110 RFLP fingerprints of the Beijing clinical isolates sequenced in this study.
Figure 2
Figure 2
Positions of IS6110 insertion sites. Dashed lines indicate identical sites. Asterisks indicate sites where there are two or more close but distinct insertions separated by 27-663 bp.
Figure 3
Figure 3
Substitutions at synonymous sites categorized by specific base-pair replacements, showing a similar preference for G:C to A:T transversions among isolates of the R86 cluster and R220 cluster as for other mycobacterial strains such as CDC1551 and F11. All substitutions were based on comparison to H37Rv. The total number of synonymous SNPs analyzed was 112, 126, and 537 for R86, R220, and CDC1551/F11, respectively.
Figure 4
Figure 4
Phylogenetic tree constructed from 727 SNPs (excluding those related to drug resistance) by maximum parsimony (a), and also displayed as a cladogram (b) showing the number of changes (unique SNPs) associated with each branch.
Figure 5
Figure 5
Mutations in gyrA related to fluoroquinolone resistance. Ofloxacin-resistant strains are boxed; Ofl-sensitive strains are encircled; other strains were not tested by DST.
Figure 6
Figure 6
Mutations in rpoB related to rifampicin resistance.
Figure 7
Figure 7
Mutations in inhA and katG related to isoniazid resistance. All strains except HN878 are isoniazid-resistant.
Figure 8
Figure 8
Mutations in rrs and rpsL related to aminoglycoside resistance. Kan = kanamycin, Ami = amikacin, Cap = capreomycin, Str = streptomycin. R = resistant. S = sensitive. Blank means not tested.
Figure 9
Figure 9
Mutations in embB related to ethambutol resistance. The mutations are shown as codons replacing Met306 (atg).
See this image and copyright information in PMC

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