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    Apr 17, 2021
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    Whole Genome Sequencing Reveals Complex Evolution Patterns of Multidrug-Resistant Mycobacterium tuberculosis Beijing Strains in Patients

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    Name:
    Merker et al-2013-Whole Genome ...
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    Authors
    Merker, M
    Kohl, T A
    Roetzer, A
    Truebe, L
    Richter, E
    Rüsch-Gerdes, S
    Fattorini, L
    Oggioni, M R
    Cox, H
    Varaine, F
    Niemann, S
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    Affiliation
    Molecular Mycobacteriology, Research Center Borstel, Borstel, Germany
    Issue Date
    2013-12
    
    Metadata
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    Journal
    PLoS One
    Abstract
    Multidrug-resistant (MDR) Mycobacterium tuberculosis complex (MTBC) strains represent a major threat for tuberculosis (TB) control. Treatment of MDR-TB patients is long and less effective, resulting in a significant number of treatment failures. The development of further resistances leads to extensively drug-resistant (XDR) variants. However, data on the individual reasons for treatment failure, e.g. an induced mutational burst, and on the evolution of bacteria in the patient are only sparsely available. To address this question, we investigated the intra-patient evolution of serial MTBC isolates obtained from three MDR-TB patients undergoing longitudinal treatment, finally leading to XDR-TB. Sequential isolates displayed identical IS6110 fingerprint patterns, suggesting the absence of exogenous re-infection. We utilized whole genome sequencing (WGS) to screen for variations in three isolates from Patient A and four isolates from Patient B and C, respectively. Acquired polymorphisms were subsequently validated in up to 15 serial isolates by Sanger sequencing. We determined eight (Patient A) and nine (Patient B) polymorphisms, which occurred in a stepwise manner during the course of the therapy and were linked to resistance or a potential compensatory mechanism. For both patients, our analysis revealed the long-term co-existence of clonal subpopulations that displayed different drug resistance allele combinations. Out of these, the most resistant clone was fixed in the population. In contrast, baseline and follow-up isolates of Patient C were distinguished each by eleven unique polymorphisms, indicating an exogenous re-infection with an XDR strain not detected by IS6110 RFLP typing. Our study demonstrates that intra-patient microevolution of MDR-MTBC strains under longitudinal treatment is more complex than previously anticipated. However, a mutator phenotype was not detected. The presence of different subpopulations might confound phenotypic and molecular drug resistance tests. Furthermore, high resolution WGS analysis is necessary to accurately detect exogenous re-infection as classical genotyping lacks discriminatory power in high incidence settings.
    Publisher
    Public Library of Science
    URI
    http://hdl.handle.net/10144/311609
    DOI
    10.1371/journal.pone.0082551
    PubMed ID
    24324807
    Language
    en
    ISSN
    1932-6203
    ae974a485f413a2113503eed53cd6c53
    10.1371/journal.pone.0082551
    Scopus Count
    Collections
    TB

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