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


CONCLUSIONS
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.
Department of Computer Science and Engineering, Texas A&M University, College Station, TX, USA. ioerger@cs.tamu.edu
Thomas R
TR
Ioerger
Yicheng
Y
Feng
Xiaohua
X
Chen
Karen M
KM
Dobos
Thomas C
TC
Victor
Elizabeth M
EM
Streicher
Robin M
RM
Warren
Nicolaas C
NC
Gey van Pittius
Paul D
PD
Van Helden
James C
JC
Sacchettini
D019943:Amino Acid Substitution / Q000235:genetics; D000995:Antitubercular Agents / Q000494:pharmacology / Q000627:therapeutic use; D002999:Clone Cells; D003062:Codon / Q000235:genetics; D024901:Drug Resistance, Multiple, Bacterial / Q000187:drug effects / Q000235:genetics*; D016680:Genome, Bacterial / Q000235:genetics; D005838:Genotype; D016254:Mutagenesis, Insertional / Q000235:genetics; D009154:Mutation / Q000235:genetics; D009169:Mycobacterium tuberculosis / Q000187:drug effects / Q000235:genetics* / Q000302:isolation & purification*; D010802:Phylogeny; D012150:Polymorphism, Restriction Fragment Length; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D017422:Sequence Analysis, DNA; D013019:South Africa; D018088:Tuberculosis, Multidrug-Resistant / Q000188:drug therapy / Q000235:genetics / Q000382:microbiology*
D000995:Antitubercular Agents; D003062:Codon