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

Authors
 Alifiya S. Motiwala  ;  Yang Dai  ;  Edward C. Jones-López  ;  Soo-Hee Hwang  ;  Jong Seok Lee  ;  Sang Nae Cho  ;  Laura E. Via  ;  Clifton E. Barry 3rd  ;  David Alland 
Citation
 JOURNAL OF INFECTIOUS DISEASES, Vol.201(6) : 881-888, 2010 
Journal Title
 JOURNAL OF INFECTIOUS DISEASES 
ISSN
 0022-1899 
Issue Date
2010
MeSH
Antitubercular Agents/pharmacology* ; Antitubercular Agents/therapeutic use ; Databases, Nucleic Acid ; Drug Resistance, Multiple, Bacterial/genetics* ; Extensively Drug-Resistant Tuberculosis/complications ; Extensively Drug-Resistant Tuberculosis/microbiology* ; Genes, MDR ; HIV Infections/complications ; Humans ; Mutation/drug effects ; Mutation/genetics* ; Mycobacterium tuberculosis/classification ; Mycobacterium tuberculosis/drug effects ; Mycobacterium tuberculosis/genetics* ; Phylogeny ; Polymerase Chain Reaction ; Polymorphism, Genetic
Keywords
mutation ; drug resistance ; disease outbreaks ; genes ; genome ; mycobacterium tuberculosis ; tuberculosis ; de novo mutation
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.
Files in This Item:
T201003007.pdf Download
DOI
10.1086/650999
Appears in Collections:
1. College of Medicine (의과대학) > Dept. of Microbiology (미생물학교실) > 1. Journal Papers
Yonsei Authors
Cho, Sang Nae(조상래)
URI
https://ir.ymlib.yonsei.ac.kr/handle/22282913/101956
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