Mutations in extensively drug-resistant mycobacterium tuberculosis that do not code for known drug-resistance mechanisms

Alifiya S. Motiwala, Yang Dai, Edward C. Jones-López, Soo Hee Hwang, Jong Seok Lee, Sang Nae Cho, Laura E. Via, Clifton E. Barry, David Alland

Research output: Contribution to journalArticle

16 Citations (Scopus)

Abstract

Background. Highly lethal outbreaks of multidrug-resistant (MDR) and extensively drug-resistant (XDR) tuberculosis are increasing. Whole-genome sequencing of KwaZulu-Natal MDR and XDR outbreak strains prevalent in human immunodeficiency virus (HIV)-infected patients by the Broad Institute identified 22 novel mutations which were unique to the XDR genome or shared only by the MDR and XDR genomes and not already known to be associated with drug resistance. Methods. We studied the 12 novel mutations which were not located in highly-repetitive genes to identify mutations that were truly associated with drug resistance or were likely to confer a specific fitness advantage. Results. None of these mutations could be found in a phylogenetically and geographically diverse set of drug-resistant and drug-susceptible Mycobacterium tuberculosis isolates, suggesting that these mutations are unique to the KZN clone. Examination of the 600-basepair region flanking each mutation revealed 26 new mutations. We searched for a convergent evolutionary signal in the new mutations for evidence that they emerged under selective pressure, consistent with increased fitness. However, all but 1 rare mutation were monophyletic, indicating that the mutations were markers of strain phylogeny rather than fitness or drug resistance. Conclusions. Our results suggest that virulent XDR tuberculosis in immunocompromised HIV-infected patients can evolve without generalizable fitness changes or other XDR-specific mutations.

Original languageEnglish
Pages (from-to)881-888
Number of pages8
JournalJournal of Infectious Diseases
Volume201
Issue number6
DOIs
Publication statusPublished - 2010 Mar 12

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Extensively Drug-Resistant Tuberculosis
Mycobacterium tuberculosis
Drug Resistance
Mutation
Genome
Disease Outbreaks
HIV
Phylogeny
Pharmaceutical Preparations

All Science Journal Classification (ASJC) codes

  • Immunology and Allergy
  • Infectious Diseases

Cite this

Motiwala, Alifiya S. ; Dai, Yang ; Jones-López, Edward C. ; Hwang, Soo Hee ; Lee, Jong Seok ; Cho, Sang Nae ; Via, Laura E. ; Barry, Clifton E. ; Alland, David. / Mutations in extensively drug-resistant mycobacterium tuberculosis that do not code for known drug-resistance mechanisms. In: Journal of Infectious Diseases. 2010 ; Vol. 201, No. 6. pp. 881-888.
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Motiwala, AS, Dai, Y, Jones-López, EC, Hwang, SH, Lee, JS, Cho, SN, Via, LE, Barry, CE & Alland, D 2010, 'Mutations in extensively drug-resistant mycobacterium tuberculosis that do not code for known drug-resistance mechanisms', Journal of Infectious Diseases, vol. 201, no. 6, pp. 881-888. https://doi.org/10.1086/650999

Mutations in extensively drug-resistant mycobacterium tuberculosis that do not code for known drug-resistance mechanisms. / Motiwala, Alifiya S.; Dai, Yang; Jones-López, Edward C.; Hwang, Soo Hee; Lee, Jong Seok; Cho, Sang Nae; Via, Laura E.; Barry, Clifton E.; Alland, David.

In: Journal of Infectious Diseases, Vol. 201, No. 6, 12.03.2010, p. 881-888.

Research output: Contribution to journalArticle

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AU - Motiwala, Alifiya S.

AU - Dai, Yang

AU - Jones-López, Edward C.

AU - Hwang, Soo Hee

AU - Lee, Jong Seok

AU - Cho, Sang Nae

AU - Via, Laura E.

AU - Barry, Clifton E.

AU - Alland, David

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N2 - Background. Highly lethal outbreaks of multidrug-resistant (MDR) and extensively drug-resistant (XDR) tuberculosis are increasing. Whole-genome sequencing of KwaZulu-Natal MDR and XDR outbreak strains prevalent in human immunodeficiency virus (HIV)-infected patients by the Broad Institute identified 22 novel mutations which were unique to the XDR genome or shared only by the MDR and XDR genomes and not already known to be associated with drug resistance. Methods. We studied the 12 novel mutations which were not located in highly-repetitive genes to identify mutations that were truly associated with drug resistance or were likely to confer a specific fitness advantage. Results. None of these mutations could be found in a phylogenetically and geographically diverse set of drug-resistant and drug-susceptible Mycobacterium tuberculosis isolates, suggesting that these mutations are unique to the KZN clone. Examination of the 600-basepair region flanking each mutation revealed 26 new mutations. We searched for a convergent evolutionary signal in the new mutations for evidence that they emerged under selective pressure, consistent with increased fitness. However, all but 1 rare mutation were monophyletic, indicating that the mutations were markers of strain phylogeny rather than fitness or drug resistance. Conclusions. Our results suggest that virulent XDR tuberculosis in immunocompromised HIV-infected patients can evolve without generalizable fitness changes or other XDR-specific mutations.

AB - Background. Highly lethal outbreaks of multidrug-resistant (MDR) and extensively drug-resistant (XDR) tuberculosis are increasing. Whole-genome sequencing of KwaZulu-Natal MDR and XDR outbreak strains prevalent in human immunodeficiency virus (HIV)-infected patients by the Broad Institute identified 22 novel mutations which were unique to the XDR genome or shared only by the MDR and XDR genomes and not already known to be associated with drug resistance. Methods. We studied the 12 novel mutations which were not located in highly-repetitive genes to identify mutations that were truly associated with drug resistance or were likely to confer a specific fitness advantage. Results. None of these mutations could be found in a phylogenetically and geographically diverse set of drug-resistant and drug-susceptible Mycobacterium tuberculosis isolates, suggesting that these mutations are unique to the KZN clone. Examination of the 600-basepair region flanking each mutation revealed 26 new mutations. We searched for a convergent evolutionary signal in the new mutations for evidence that they emerged under selective pressure, consistent with increased fitness. However, all but 1 rare mutation were monophyletic, indicating that the mutations were markers of strain phylogeny rather than fitness or drug resistance. Conclusions. Our results suggest that virulent XDR tuberculosis in immunocompromised HIV-infected patients can evolve without generalizable fitness changes or other XDR-specific mutations.

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