Evolution of extensively drug-resistant tuberculosis over four decades revealed by whole genome sequencing of Mycobacterium tuberculosis from KwaZulu-Natal, South Africa

Keira A. Cohen, Thomas Abeel, Abigail Manson McGuire, Christopher A. Desjardins, Vanisha Munsamy, Terrance P. Shea, Bruce J. Walker, Nonkqubela Bantubani, Deepak V. Almeida, Lucia Alvarado, Sinead Chapman, Nomonde R. Mvelase, Eamon Y. Duffy, Michael G. Fitzgerald, Pamla Govender, Sharvari Gujja, Susanna Hamilton, Clint Howarth, Jeffrey D. Larimer, Kasmheel MaharajMatthew D. Pearson, Margaret E. Priest, Qiandong Zeng, Nesri Padayatchi, Jacques Grosset, Sarah K. Young, Jennifer Wortman, Koleka P. Mlisana, Max R. O'Donnell, Bruce W. Birren, William R. Bishai, Alexander S. Pym, Ashlee M. Earl

Research output: Contribution to journalArticle


The largest global outbreak of extensively drug-resistant (XDR) tuberculosis (TB) was identified in Tugela Ferry, KwaZulu-Natal (KZN), South Africa in 2005. The antecedents and timing of the emergence of drug resistance in this fatal epidemic XDR outbreak are unknown, and it is unclear whether drug resistance in this region continues to be driven by clonal spread or by the development of de novo resistance. A whole genome sequencing and drug susceptibility testing (DST) was performed on 337 clinical isolates of Mycobacterium tuberculosis (M.tb) collected in KZN from 2008 to 2013, in addition to three historical isolates, one of which was isolated during the Tugela Ferry outbreak. Using a variety of whole genome comparative approaches, 11 drug-resistant clones of M.tb circulating from 2008 to 2013 were identified, including a 50-member clone of XDR M.tb that was highly related to the Tugela Ferry XDR outbreak strain. It was calculated that the evolutionary trajectory from first-line drug resistance to XDR in this clone spanned more than four decades and began at the start of the antibiotic era. It was also observed that frequent de novo evolution of MDR and XDR was present, with 56 and 9 independent evolutions, respectively. Thus, ongoing amplification of drug-resistance in KwaZulu-Natal is driven by both clonal spread and de novo acquisition of resistance. In drug-resistant TB, isoniazid resistance was overwhelmingly the initial resistance mutation to be acquired, which would not be detected by current rapid molecular diagnostics that assess only rifampicin resistance.

Original languageEnglish (US)
JournalInternational Journal of Mycobacteriology
Publication statusAccepted/In press - 2015



  • South Africa
  • Tuberculosis

ASJC Scopus subject areas

  • Infectious Diseases
  • Microbiology (medical)

Cite this