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Genomic analysis of the emergence of drug-resistant strains of Mycobacterium tuberculosis in the Middle East.

ABSTRACT: Tuberculosis (TB) represents a significant challenge to public health authorities, especially with the emergence of drug-resistant (DR) and multidrug-resistant (MDR) isolates of Mycobacterium tuberculosis. We sought to examine the genomic variations among recently isolated strains of M. tuberculosis in two closely related countries with different population demography in the Middle East. Clinical isolates of M. tuberculosis from both Egypt and Saudi Arabia were subjected to phenotypic and genotypic analysis on gene and genome-wide levels. Isolates with MDR phenotypes were highly prevalent in Egypt (up to 35%) despite its relatively stable population structure (sympatric pattern). MDR-TB isolates were not identified in the isolates from Saudi Arabia despite its active guest worker program (allopatric pattern). However, tuberculosis isolates from Saudi Arabia, where lineage 4 was more prevalent (>65%), showed more diversity than isolates from Egypt, where lineage 3 was the most prevalent (>75%). Phylogenetic and molecular dating analyses indicated that lineages from Egypt were recently diverged (~78 years), whereas those from Saudi Arabia were diverged by over 200 years. Interestingly, DR isolates did not appear to cluster together or spread more widely than drug-sensitive isolates, suggesting poor treatment as the main cause for emergence of drug resistance rather than more virulence or more capacity to persist.

SUBMITTER: Alyamani EJ

PROVIDER: S-EPMC6418154 | biostudies-literature | 2019 Mar

REPOSITORIES: biostudies-literature

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Project description:Tuberculosis caused by multidrug-resistant (MDR) and extensively drug-resistant (XDR) Mycobacterium tuberculosis (MTB) strains is a growing problem in many countries. The availability of the complete nucleotide sequences of several MTB genomes allows to use the comparative genomics as a tool to study the relationships of strains and differences in their evolutionary history including acquisition of drug-resistance. In our work, we sequenced three genomes of Russian MTB strains of different phenotypes--drug susceptible, MDR and XDR. Of them, MDR and XDR strains were collected in Tomsk (Siberia, Russia) during the local TB outbreak in 1998-1999 and belonged to rare KQ and KY families in accordance with IS6110 typing, which are considered endemic for Russia. Based on phylogenetic analysis, our isolates belonged to different genetic families, Beijing, Ural and LAM, which made the direct comparison of their genomes impossible. For this reason we performed their comparison in the broader context of all M. tuberculosis genomes available in GenBank. The list of unique individual non-synonymous SNPs for each sequenced isolate was formed by comparison with all SNPs detected within the same phylogenetic group. For further functional analysis, all proteins with unique SNPs were ascribed to 20 different functional classes based on Clusters of Orthologous Groups (COG). We have confirmed drug resistant status of our isolates that harbored almost all known drug-resistance associated mutations. Unique SNPs of an XDR isolate CTRI-4(XDR), belonging to a Beijing family were compared in more detail with SNPs of additional 14 Russian XDR strains of the same family. Only type specific mutations in genes of repair, replication and recombination system (COG category L) were found common within this group. Probably the other unique SNPs discovered in CTRI-4(XDR) may have an important role in adaptation of this microorganism to its surrounding and in escape from antituberculosis drugs treatment.

Project description:Tuberculosis (TB) remains as one of the deadliest diseases after HIV globally with 95 % of deaths confined to low-and-middle income countries. Pakistan is fifth among the 22 high-burden TB countries with the incidence rate of 230/100,000 persons, however, studies related to prevalent Mycobacterium tuberculosis strains and their spread, drug resistance pattern and evolutionary genetics are inadequate. The present study was undertaken to highlight the circulation of M. tuberculosis strains causing drug resistant TB in our community by targeting the molecular marker IS6110 and then characterization of these strains as Beijing and Non-Beijing genotypes. Sputum samples from 102 MDR TB suspects from different cities of Punjab were collected and their record was stored in a database. Sputum samples were evaluated by Ziehl Neelson staining and cultured on Lownstein Jensen medium by Modified Petroff's method. DST was performed for first-line anti-mycobacterial drugs by indirect proportion method. Mycobacterium tuberculosis isolates were investigated for the presence of IS6110 and further identification as Beijing, Non-Beijing or mixed genotype. Percentage of male and female patients was found to be 58.8 and 41.2 % respectively. DST showed resistance of 93 % of isolates to isoniazid and rifampicin. All of the isolates showed positive results for IS6110 amplification. Based on PCR amplification of Beijing and non-Beijing primer sets 4.9 % of the patients showed infection with pure Beijing isolates, 14.7 % with both Beijing and non-Beijing isolates and 80.3 % with pure non-Beijing isolates. Analysis of IS6110 and Beijing sequences showed the presence of putative transposase conserved domain while non-Beijing sequences were epitomized with RAMP_I_III superfamily domain (CRISPR-associated protein family). TB in Pakistan is predominantly caused by Non-Beijing genotypes, but Beijing strains showed incessant circulation in our community as both single and mixed (co-infecting Non-Beijing and Beijing) strains.

Project description:BackgroundTuberculosis is a serious infectious disease affecting millions of people. In spite of efforts to reduce the disease, increasing antibiotic resistance has contributed to persist in the top 10 causes of death worldwide. In fact, the increased cases of multi (MDR) and extreme drug resistance (XDR) worldwide remains the main challenge for tuberculosis control. Whole genome sequencing is a powerful tool for predicting drug resistance-related variants, studying lineages, tracking transmission, and defining outbreaks. This study presents the identification and characterization of resistant clinical isolates of Mycobacterium tuberculosis including a phylogenetic and molecular resistance profile study by sequencing the complete genome of 24 strains from different provinces of Ecuador.ResultsGenomic sequencing was used to identify the variants causing resistance. A total of 15/21 isolates were identified as MDR, 4/21 as pre-XDR and 2/21 as XDR, with three isolates discarded due to low quality; the main sub-lineage was LAM (61.9%) and Haarlem (19%) but clades X, T and S were identified. Of the six pre-XDR and XDR strains, it is noteworthy that five come from females; four come from the LAM sub-lineage and two correspond to the X-class sub-lineage. A core genome of 3,750 genes, distributed in 295 subsystems, was determined. Among these, 64 proteins related to virulence and implicated in the pathogenicity of M. tuberculosis and 66 possible pharmacological targets stand out. Most variants result in nonsynonymous amino acid changes and the most frequent genotypes were identified as conferring resistance to rifampicin, isoniazid, ethambutol, para-aminosalicylic acid and streptomycin. However, an increase in the resistance to fluoroquinolones was detected.ConclusionThis work shows for the first time the variability of circulating resistant strains between men and women in Ecuador, highlighting the usefulness of genomic sequencing for the identification of emerging resistance. In this regard, we found an increase in fluoroquinolone resistance. Further sampling effort is needed to determine the total variability and associations with the metadata obtained to generate better health policies.

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Genomic analysis of the emergence of drug-resistant strains of Mycobacterium tuberculosis in the Middle East.

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