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Title: Prevalence and extent of heteroresistance by next generation sequencing of multidrug-resistant tuberculosis
Authors: Darwin J. Operario
Alexander F. Koeppel
Stephen D. Turner
Yongde Bao
Suporn Pholwat
Sayera Banu
Suporn Foongladda
Stellah Mpagama
Jean Gratz
Oleg Ogarkov
Svetlana Zhadova
Scott K. Heysell
Eric R. Houpt
University of Virginia
International Centre for Diarrhoeal Disease Research Bangladesh
Mahidol University
Kibong'oto Infectious Diseases Hospital
Scientific Сentre for Family Health and Human Reproduction Problems
Keywords: Agricultural and Biological Sciences;Biochemistry, Genetics and Molecular Biology
Issue Date: 1-May-2017
Citation: PLoS ONE. Vol.12, No.5 (2017)
Abstract: © 2017 Operario et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Amplicon-based Next Generation Sequencing (NGS) is an emerging method for Mycobacterium tuberculosis drug susceptibility testing (DST) but has not been well described. We examined 158 clinical multidrug-resistant M. tuberculosis isolates via NGS of 11 resistance-associated gene regions covering 3519 nucleotides. Across these gene regions, complete resistance or heteroresistance (defined as 1%-99% mutation) was present in at least one isolate in 6.3% of loci. The number of isolates with heteroresistance was highest for gyrA codon 94, rpoB codons 526 and 531, and embB codons 306, 372 and 406 (range 11-26% of isolates exhibited heteroresistance). 57% of MDR strains had heteroresistance of one or more recognized resistance-associated mutation. Heteroresistant loci generally exhibited high or low degrees of mutation (>90% or <10%). The deep sensitivity of NGS for detecting low level pncA heteroresistance appeared to improve genotypic-phenotypic PZA susceptibility correlations over that of Sanger. NGS demonstrates that heteroresistance in TB in the regions of key genes is common and will need to be bioinformatically managed. The clinical significance of such heteroresistance is unclear, and further study of pncA should be pursued.
ISSN: 19326203
Appears in Collections:Scopus 2016-2017

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