Whole Genome Sequencing Based Characterization of Extensively Drug-Resistant Mycobacterium tuberculosis Isolates from Pakistan
Hill-Cawthorne, Grant A.
Clark, Taane G.
KAUST DepartmentBiological and Environmental Sciences and Engineering (BESE) Division
Computational Bioscience Research Center (CBRC)
Pathogen Genomics Laboratory
Permanent link to this recordhttp://hdl.handle.net/10754/346687
MetadataShow full item record
AbstractImproved molecular diagnostic methods for detection drug resistance in Mycobacterium tuberculosis (MTB) strains are required. Resistance to first- and second- line anti-tuberculous drugs has been associated with single nucleotide polymorphisms (SNPs) in particular genes. However, these SNPs can vary between MTB lineages therefore local data is required to describe different strain populations. We used whole genome sequencing (WGS) to characterize 37 extensively drug-resistant (XDR) MTB isolates from Pakistan and investigated 40 genes associated with drug resistance. Rifampicin resistance was attributable to SNPs in the rpoB hot-spot region. Isoniazid resistance was most commonly associated with the katG codon 315 (92%) mutation followed by inhA S94A (8%) however, one strain did not have SNPs in katG, inhA or oxyR-ahpC. All strains were pyrazimamide resistant but only 43% had pncA SNPs. Ethambutol resistant strains predominantly had embB codon 306 (62%) mutations, but additional SNPs at embB codons 406, 378 and 328 were also present. Fluoroquinolone resistance was associated with gyrA 91-94 codons in 81% of strains; four strains had only gyr B mutations, while others did not have SNPs in either gyrA or gyrB. Streptomycin resistant strains had mutations in ribosomal RNA genes; rpsL codon 43 (42%); rrs 500 region (16%), and gidB (34%) while six strains did not have mutations in any of these genes. Amikacin/kanamycin/capreomycin resistance was associated with SNPs in rrs at nt1401 (78%) and nt1484 (3%), except in seven (19%) strains. We estimate that if only the common hot-spot region targets of current commercial assays were used, the concordance between phenotypic and genotypic testing for these XDR strains would vary between rifampicin (100%), isoniazid (92%), flouroquinolones (81%), aminoglycoside (78%) and ethambutol (62%); while pncA sequencing would provide genotypic resistance in less than half the isolates. This work highlights the importance of expanded targets for drug resistance detection in MTB isolates.
CitationWhole Genome Sequencing Based Characterization of Extensively Drug-Resistant Mycobacterium tuberculosis Isolates from Pakistan 2015, 10 (2):e0117771 PLOS ONE
PublisherPublic Library of Science (PLoS)
PubMed Central IDPMC4342168
- Characterization of mutations in multi- and extensive drug resistance among strains of Mycobacterium tuberculosis clinical isolates in Republic of Korea.
- Authors: Jnawali HN, Hwang SC, Park YK, Kim H, Lee YS, Chung GT, Choe KH, Ryoo S
- Issue date: 2013 Jun
- Sequence analysis for detection of drug resistance in Mycobacterium tuberculosis complex isolates from the Central Region of Cameroon.
- Authors: Tekwu EM, Sidze LK, Assam JP, Tedom JC, Tchatchouang S, Makafe GG, Wetewale AL, Kuaban C, Eyangoh S, Ntoumi F, Beng VN, Frank M
- Issue date: 2014 May 3
- Characterization of mutations conferring extensive drug resistance to Mycobacterium tuberculosis isolates in Pakistan.
- Authors: Ali A, Hasan R, Jabeen K, Jabeen N, Qadeer E, Hasan Z
- Issue date: 2011 Dec
- Molecular characterization of mutations associated with resistance to second-line tuberculosis drug among multidrug-resistant tuberculosis patients from high prevalence tuberculosis city in Morocco.
- Authors: Oudghiri A, Karimi H, Chetioui F, Zakham F, Bourkadi JE, Elmessaoudi MD, Laglaoui A, Chaoui I, El Mzibri M
- Issue date: 2018 Feb 27
- Mechanisms of first-line antimicrobial resistance in multi-drug and extensively drug resistant strains of Mycobacterium tuberculosis in KwaZulu-Natal, South Africa.
- Authors: Dookie N, Sturm AW, Moodley P
- Issue date: 2016 Oct 26