Analysis of Serial Multidrug-Resistant Tuberculosis Strains Causing Treatment Failure and Within-Host Evolution by Whole-Genome Sequencing

Chen, Xinchang; He, Guiqing; Lin, Siran; Wang, Shiyong; Sun, Feng; Chen, Jiazhen; Zhang, Wenhong

doi:10.1128/msphere.00884-20

Cited by 15 publications

(19 citation statements)

References 47 publications

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“…Although allelic variation in some other genes was observed in this configuration, it was transient and was not observed to be fixed in the dominant population. This is consistent with other studies documenting long-term infections, with no changes in the presence of fixed SNPs in populations of M. tuberculosis [37,38].…”

Section: Discussionsupporting

confidence: 93%

SNPs in genes related to the repair of damage to DNA in clinical isolates ofM. tuberculosis: a transversal and longitudinal approach

Pérez-Martínez,

Zenteno-Cuevas

2023

Preprint

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The presence of SNPs in genes related to DNA damage repair inM. tuberculosiscan trigger hypermutagenic phenotypes with a higher probability of generating drug resistance. The aim of this research was to compare the presence of SNPs in genes related to DNA damage repair between sensitive and DR isolates, as well as to describe the dynamics in the presence of SNPs inM. tuberculosisisolated from recently diagnosed TB patients of the state of Veracruz, Mexico. The presence of SNPs in the coding regions of 65 genes related to DNA damage repair was analyzed. Eighty-six isolates from 67 patients from central Veracruz state, Mexico, were sequenced. The results showed several SNPs in 14 genes that were only present in drug-resistant genomes. In addition, by following of 15 patients, it was possible to describe three different dynamics of appearance and evolution of non-synonymous SNPs in genes related to DNA damage repair: 1) constant fixed SNPs, 2) population substitution, and 3) gain of fixed SNPs. Further research is required to discern the biological significance of each of these pathways and their utility as markers of DR or for treatment prognosis.

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Section: Discussionsupporting

confidence: 93%

SNPs in genes related to the repair of damage to DNA in clinical isolates ofM. tuberculosis: a transversal and longitudinal approach

Pérez-Martínez,

Zenteno-Cuevas

2023

Preprint

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“…Therefore, these regions should not be considered in SNP calling. and recurrence was classified as being due to relapse if there was a difference of ≤6 SNPs ( Cock et al, 2010 ; Jiang et al, 2011 ; Chen et al, 2020 ; Shanmugam et al, 2021 ). A minimum spanning tree was constructed based on pairwise whole-genome SNP differences using BioNumerics (Version5.…”

Section: Methodsmentioning

confidence: 99%

Distinguishing Relapse From Reinfection With Whole-Genome Sequencing in Recurrent Pulmonary Tuberculosis: A Retrospective Cohort Study in Beijing, China

Liu

et al. 2021

Front. Microbiol.

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Background: Tuberculosis recurrence is still a major problem for the control of tuberculosis, and the cause of the recurrence is still unclear.Methods: We retrospectively recruited 68 pairs of samples of Mycobacterium tuberculosis (MTB) from recurrent TB cases in Beijing Chest Hospital between January 2008 and December 2019. The whole-genome sequencing was conducted to analyze single-nucleotide polymorphism (SNP) and to identify whether recurrent disease was due to relapse or reinfection. The BACTEC MGIT was performed to compare differences in drug susceptibility profiles between two episodes.Results: 62 (91.2%) out of 68 confirmed recurrence were due to relapse, whereas the remaining six (8.8%) were due to reinfection. And there was a strong association between earlier relapse and underlying chronic diseases. In addition, the MTB isolates from non-diabetic patients had a higher mutation rate than those from diabetic patients. A community transmission was also identified in our cohort. Levofloxacin resistance was the most frequently observed drug resistance for 12.9% relapse cases.Conclusion: The relapse of a previous episode in Beijing. The underlying chronic diseases are associated with an earlier TB relapse. MTB isolates were more prone to develop levofloxacin resistance than moxifloxacin resistance after FQ exposure. The patients at high-risk for relapses deserve more careful investigation.

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“… 27–29 Several studies have also shown these gyrA variants to emerge during treatment and to be associated with treatment failure. 7 , 9 , 30 , 31 In this study, we report on clonal interference between the D94G and D94N variants in patient 5 at month 4 with frequencies of 62.16% and 32.35%, respectively, until month 7 when only the D94G variant was present at 100% frequency and dominated the population ( Figure 2 ). While treatment failure was already reported clinically and microbiologically at month 6 for patient 3, we did not detect resistance acquisition genotypically and phenotypically until month 8.…”

Section: Discussionmentioning

confidence: 70%

Mycobacterium tuberculosis Intra-Host Evolution Among Drug-Resistant Tuberculosis Patients Failing Treatment

Perumal¹,

Khan²,

Naidoo³

et al. 2023

IDR

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Background Understanding Mycobacterium tuberculosis ( Mtb ) intra-host evolution of drug resistance is important for successful drug-resistant tuberculosis (DR-TB) treatment and control strategies. This study aimed to characterise the acquisition of genetic mutations and low-frequency variants associated with treatment-emergent Mtb drug resistance in longitudinally profiled clinical isolates from patients who experienced DR-TB treatment failure. Patients and Methods We performed deep Whole Genome Sequencing on 23 clinical isolates obtained longitudinally across nine timepoints from five patients who experienced DR-TB treatment failure enrolled in the CAPRISA 020 InDEX study. The minimum inhibitory concentrations (MICs) were established on the BACTEC™ MGIT 960™ instrument on 15/23 longitudinal clinical isolates for eight anti-TB drugs (rifampicin, isoniazid, ethambutol, levofloxacin, moxifloxacin, linezolid, clofazimine, bedaquiline). Results In total, 22 resistance associated mutations/variants were detected. We observed four treatment-emergent mutations in two out of the five patients. Emerging resistance to the fluoroquinolones was associated with 16- and 64-fold elevated levofloxacin (2–8 mg/L) and moxifloxacin (1–2 mg/L) MICs, respectively, resulting from the D94G/N and A90V variants in the gyrA gene. We identified two novel mutations associated with elevated bedaquiline MICs (>66-fold): an emerging frameshift variant (D165) on the Rv0678 gene and R409Q variant on the Rv1979c gene present from baseline. Conclusion Genotypic and phenotypic resistance to the fluoroquinolones and bedaquiline was acquired in two out of five patients who experienced DR-TB treatment failure. Deep sequencing of multiple longitudinal clinical isolates for resistance-associated mutations coupled with phenotypic MIC testing confirmed intra-host Mtb evolution.

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Analysis of Serial Multidrug-Resistant Tuberculosis Strains Causing Treatment Failure and Within-Host Evolution by Whole-Genome Sequencing

Cited by 15 publications

References 47 publications

SNPs in genes related to the repair of damage to DNA in clinical isolates ofM. tuberculosis: a transversal and longitudinal approach

SNPs in genes related to the repair of damage to DNA in clinical isolates ofM. tuberculosis: a transversal and longitudinal approach

Distinguishing Relapse From Reinfection With Whole-Genome Sequencing in Recurrent Pulmonary Tuberculosis: A Retrospective Cohort Study in Beijing, China

Mycobacterium tuberculosis Intra-Host Evolution Among Drug-Resistant Tuberculosis Patients Failing Treatment

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