|Year : 2012 | Volume
| Issue : 3 | Page : 124-130
Drug resistance-related mutations in multidrug-resistant Mycobacterium tuberculosis isolates from diverse geographical regions
Senia Rosales-Klintz1, Pontus Jureen2, Aksana Zalutskayae3, Alena Skrahina3, Biao Xu4, Yi Hu4, Lelany Pineda-Garcia5, Muayad Aghali Merza6, Ionela Muntean7, Freddie Bwanga8, Moses Joloba8, Sven E Hoffner2
1 Escuela de Microbiologia, Universidad Nacional Autonoma de , Tegucigalpa, ; Division of Global Health (IHCAR), Karolinska Institutet, Stockholm; Department of Preparedness, Swedish Institute for Communicable Disease Control, Solna, Sweden, Honduras
2 Department of Preparedness, Swedish Institute for Communicable Disease Control, Solna; Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, Stockholm, Sweden
3 Republican Scientific and Practical Center for Pulmonology and Phthisiology, Minsk, Belarus
4 School of Public Health, Fudan University, Shanghai, PR China
5 Escuela de Microbiologia, Universidad Nacional Autonoma de , Tegucigalpa, Honduras
6 Azadi Teaching Hospital, College of Medicine, University of Dohuk, Dohuk, Iraq; National Research Institute of TB and Lung Disease, Tehran, Iran
7 Hospital of Pneumophtisiology, Brasov, Romania
8 Department of Medical Microbiology, School of Medical Sciences, Makerere University, Kampala, Uganda
|Date of Web Publication||28-Feb-2017|
Sven E Hoffner
Swedish Institute for Communicable Disease Control, SE 171-82 Solna
Source of Support: None, Conflict of Interest: None
Background: Drug resistance in Mycobacterium tuberculosis is associated with chromosomal mutations in selected genes. These mutations can be screened for an early warning system for drug-resistant tuberculosis. The prevalence of individual mutations differs geographically, which must be considered in developing globally applicable screening tests.
Methods: In order to analyse the geographical distribution and frequency of mutations conferring resistance to rifampicin, isoniazid and fluoroquinolones, the researchers investigated the presence of mutations in the rpoB gene, the katG gene, the mabA-inhA promoter region and the gyrA gene in clinical isolates of multidrug-resistant tuberculosis (MDR-TB) from Belarus, China, Iran/Iraq, Honduras, Romania and Uganda. For each study site, the researchers described the distribution of specific mutations in 20 clinical MDR-isolates.
Results: The distribution of resistance-related mutations varied significantly between the study sites. Settings with a high incidence of MDR-TB, such as Belarus, showed a narrower spectrum of mutations related to rifampicin and isoniazid resistance and also a higher prevalence of fluoroquinolone resistance than study sites with a lower MDR-TB prevalence.
Conclusion: This study confirms that there are significant geographical differences in the distribution of resistance-related mutations and suggests that an increased understanding of such differences in the specific distribution of resistance conferring mutations is crucial for development of new, generally applicable, molecular tools for rapid diagnosis of drug-resistant TB. The fact that a narrower distribution of mutations in high MDR-TB prevalence settings was seen suggests that much of the problems in these settings can be a result of an ongoing transmission of certain MDR-TB strains.
Keywords: MDR-TB, rpoB gene, katG gene, mabA-inhA operon, gyrA gene
|How to cite this article:|
Rosales-Klintz S, Jureen P, Zalutskayae A, Skrahina A, Xu B, Hu Y, Pineda-Garcia L, Merza MA, Muntean I, Bwanga F, Joloba M, Hoffner SE. Drug resistance-related mutations in multidrug-resistant Mycobacterium tuberculosis isolates from diverse geographical regions. Int J Mycobacteriol 2012;1:124-30
|How to cite this URL:|
Rosales-Klintz S, Jureen P, Zalutskayae A, Skrahina A, Xu B, Hu Y, Pineda-Garcia L, Merza MA, Muntean I, Bwanga F, Joloba M, Hoffner SE. Drug resistance-related mutations in multidrug-resistant Mycobacterium tuberculosis isolates from diverse geographical regions. Int J Mycobacteriol [serial online] 2012 [cited 2019 Sep 21];1:124-30. Available from: http://www.ijmyco.org/text.asp?2012/1/3/124/201236
| Introduction|| |
Globally, it is estimated that multidrug-resistant tuberculosis (MDR-TB) affects around 650,000 patients . This form of the disease is resistant to at least isoniazid (INH) and rifampicin (RIF), the main first-line drugs used for tuberculosis (TB) treatment . Mismanagement of MDR-TB treatment has caused the development of extensively drug-resistant TB (XDR-TB), defined as MDR-TB also resistant to any of the fluoroquinolones and at least one of the injectable second-line drugs . In some countries, MDR/XDR-TB constitutes a major threat to public health and jeopardizes TB control. Alarming data was recently reported from Belarus where a prevalence of MDR-TB among infectious cases in Minsk was shown to be 49%. Among newly detected patients with infectious (smear positive) pulmonary disease, 35% had MDR-TB and no less than 76% was found in previously treated cases . This is the highest level ever seen of MDR-TB and constitutes a severe challenge for TB control efforts.
Rapid and accurate detection of MDR/XDR-TB is a priority. Timely laboratory diagnosis allows for optimizing therapy and limiting transmission. This is best achieved using molecular screening for resistance-related mutations. Such molecular-based methods have been developed for the timely detection of resistance in Mycobacterium tuberculosis based on the knowledge of genetic mechanisms causing drug resistance. Several genetic biomarkers have been identified and shown to be related to phenotypic drug resistance. Among these, an 81bp region in rpoB gene contains more than 95% of the mutations seen in clinical isolates resistant to RIF ,. The katG gene ,, the promoter region of the mabA-inhA operon , have been shown to be associated with INH-resistance.
To make sure that the tests are globally applicable, researchers need to know not only which genes and mutations are responsible for resistance, but also their global distribution.
The purpose of this study was to explore the distribution of resistance-related mutations in MDR-TB isolates from seven countries on four continents.
| Materials and methods|| |
Mycobacterium tuberculosis isolates and study sites
The molecular characterization was conducted at the Swedish Institute for Communicable Disease Control (SMI), with a convenience sample of 120 clinical MDR M. tuberculosis samples collected over somewhat different time periods: Belarus (April–August 2009), China (June 2008–September 2009), Honduras (1994–1995/2004–2009), Iraq (June 2008–June 2009), Iran (May 2008–May 2009), Romania (2007–2008) and Uganda (February 2008–July 2009). Each site contributed with 20 isolates, except Iraq and Iran that contributed ten strains each.
Both the in vitro drug susceptibility testing (DST) and the DNA extraction were performed on site in each collaborating center with their respective standard technique. The DST methods used were the absolute concentration method on LÖwenstein-Jensen (LJ) medium  (Belarus, Romania) and the proportion method on LJ medium  (Iran, China, Honduras, Uganda). Bactec MGIT 960 (Becton Dickinson, Sparks, Maryland, USA)  was used for ofloxacin (OFX) testing of the Honduran isolates at SMI. The critical concentrations were 0.2/0.1 mg/L for INH, 40.0/1.0 mg/L for RIF and 2.0/2.0 mg/L for OFX for LJ and MGIT respectively. In Belarus a critical concentration of 1 mg/L was used for INH.
PCR amplification and sequencing
DNA isolation was performed as previously described ,. The DNA extracts were amplified and sequenced to identify mutations in the rifampicin resistance-determining region (RRDR) of the rpoB gene ,; the katG gene ,, the mabA-inhA promoter region  and the quinolone resistance-determining region (QRDR) in the gyrA gene ,. Polymerase chain reaction (PCR) mixtures (50μl) contained 5μl 10 × PCR buffer, 0.2 mM dNTP, 1U Ampli Taq Gold® polymerase (Applied Biosystems, USA), 0.2 mM of each appropriate pair of primers (Invitrogen, Life Technologies, UK) and 2μl of DNA extracts. PCR thermal cycling conditions and primers sequences, as well as MgCl2 concentrations used are presented in [Table 1].
|Table 1: Primers and conditions used to amplify and sequence the MDR M. tuberculosis isolates.|
Click here to view
The PCR products were verified by gel electrophoresis and purified using the GFX™ PCR DNA and gel band purification kit (GE Health Care, Amersham, Little Chalfont, UK).
The purified PCR products were sequenced using the ABI PRISM BigDye® Terminator v3.1 cycle sequencing kit and analyzed in an ABI 3130xl genetic analyzer (Applied Biosystems, CA, USA), following the manufacturer's recommendations. The DNA sequences were aligned using the CLUSTAL W algorithm . All mutations found were compared with the TBDReaMDB database .
| Results|| |
Of the total of 120 DNA extracts from MDR-TB strains contributed by the different centers, 117 (97.5%) could be genetically characterized.
A clear majority of 94% (110/117) of the MDR-TB isolates had mutations in the RRDR of rpoB. In three of the study sites all 20 isolates had rpoB mutations, while only 85% of the isolates from Romania and Iran/Iraq showed such mutations. Of all the 110 mutations detected, 89% showed single, and 5% double mutations ([Table 2]). The most frequently mutated codons were 531 and 526, found in 61 (52%) and 38 (32%) strains, respectively. The distribution of mutations related to MDR-TB differed significantly between the different settings. For example, the His526Tyr mutation was mainly found in Romanian isolates and the His526Asp mutation mostly in isolates from Belarus. No deletions or insertions were detected. [Table 2] summarizes all the rpoB mutations detected.
Most of the MDR-TB isolates (82%) had a mutation in katG and/or the mabA-inhA promoter region conferring INH-resistance. The most common mutation was katG Ser 315Thr found in 83 strains (71%), including 20 strains also showing a mabA-inhA (C-15T) mutation.
Also for INH-resistance, a distinct difference was seen in the prevalence of the mutations between the different study settings ([Table 3]). Most of the strains with mutations both in the katG gene and the mabA-inhA promoter region were from Romania and Belarus. The two isolates found with katG Ser315Thr and mabA-inhA T-8 C genotype were both from Belarus. Strains without mutations in katG or mabA-inhA were mainly from Honduras and Iraq. For one Ugandan isolate, a repeated lack of amplification was observed of the katG locus, which might indicate a deletion of this gene. A lack of mutations in rpoB, katG and mabA-inhA promoter regions were found in two isolates from Iran and two from Romania.
|Table 3: Distribution of katG and mabA-inhA promoter region mutations in 117 MDR-TB isolates.|
Click here to view
In contrast to the other drugs studied, phenotypic susceptibility data were missing for fluoroquinolones (FQs). Based on genetic characterization, the level of FQ-resistance differed significantly between the MDR-TB strains isolated in different study sites. Most frequently, FQ-related mutations were seen in isolates from Belarus and Romania, with 40% and 35% of the strains having mutations in the QRDR. In isolates from Honduras, no such mutations were seen, and in Uganda and Iran less than 10% of the MDR-isolates carried a QRDR mutation. Altogether, a total of 30 strains (26%) had mutations in the gyrA gene. Of those, 22 had FQ-resistance-related mutations in the QRDR. The most common mutation was the substitution Asp94Gly ([Table 4]).
The single substitution Thr80Ala found in eight Ugandan isolates is not considered to be related to FQ-resistance, but rather seen as an epidemiological marker.
Phenotypic DST results for FQ were only available for 56 of the MDR-TB isolates: from Belarus (20 strains), Honduras (20 strains), Romania (4 strains) and Uganda (12 strains). A full comparison between genetic and phenotypic detection of drug resistance was thus not possible.
Eight out of the nine phenotypically FQ-resistant strains detected in this subset, all from Belarus, had resistance-related mutations in the QRDR. The mutations Ala90Val and Asp94Val were the most common (3 isolates each). Among the 47 phenotypically FQ-susceptible strains, 3 had the single mutation Thr80Ala and 1 had the double mutation Thr80Ala+Asp94Gly. The remaining 43 susceptible isolates had a wild type QRDR.
Thirteen of the 61 strains without phenotypic OFX-DST results had resistance-related mutations in the QRDR. The substitution Asp94Gly was the more frequent (4/13), followed by the Ala90Val mutation (3/13). The majority of these were from Romania (7 isolates) and China (4 isolates).
The overall distribution of mutations found in gyrA is shown in [Table 4]. Taking into account the frequency of FQ-resistance-related mutations only, both Belarus and Romania have a high level of resistance with 40% and 35% of MDR-TB isolates also being resistant to FQ. In contrast, only a minority (10–20%) of the isolates from Iran/Iraq and China were resistant, whereas in the isolates from Honduras no mutations were seen in the QRDR.
Overall mutation profile
This study also analyzed whether the overall mutation profile for the 4 loci studied related to the geographic origin of the isolates. At least two mutation profiles (same mutations in all the target genes) were shared by more than three isolates from Belarus and Romania. In contrast, the profiles observed in Honduras, Iran and Uganda were more diverse.
Mutations in the studied genes were also used for classification of M. tuberculosis in phylogenetic groups. Based on katG 463 and gyrA 95 polymorphisms, the MDR-TB isolates were classified into principal genetic groups (PGGs) . One Ugandan isolate could not be categorized, owing to a lack of amplification of katG locus. Most isolates belonging to PGG1 (n = 36) were from China and Iran, reflecting the high prevalence of ancient M. tuberculosis lineages in these countries. Strains from Uganda, Honduras and Belarus belonged to the PGG2 (n = 62). The isolates within PGG3 (n = 12) were mainly from Honduras and Romania.
| Discussion|| |
As far as this study is concerned, this is the first report of mutations related to drug resistance in MDR-TB isolates from Honduras and Romania. The overall results are well in line with earlier reports from other settings on mutations related to RIF, INH and FQ-resistance ,,,,,. The mutations earlier reported to be the most common were also most frequently seen in this study. In addition, two “new” mutations were observed in katG, Arg385Pro and Ser 446Arg, which have not been reported in the TBDReaMDB database .
The most important finding of this study was that the frequency and distribution of mutations detected varied so much between the different study settings. Belarus, having the highest prevalence of MDR-TB of all the study sites, had the narrowest spectrum of RIF and INH-resistance-related mutations, while isolates from Honduras, Iran/Iraq and Uganda, where MDR-TB is much less frequent, generally had a more heterogeneous distribution of mutations. A narrow distribution might indicate an ongoing transmission of MDR.
The fact that Belarus used a higher concentration of INH (1 mg/L) in their DST might have selected for more highly resistant isolates. Mutations in katG 315 were seen in all the Belarusian isolates, a finding that has been previously reported . Consequently, it could be questioned if the lower level of INH-resistance caused by a mutation in the mabA-inhA promoter region would have been detected in the conventional DST, and thus met the criteria for inclusion in this study.
In contrast to the MDR-defining drugs, to which all included isolates were resistant, the studied isolates were included regardless of their resistance to FQ, which in most cases was unknown. Thus the level of FQ-resistance, reflected by the detection of mutations in the QRDR of the gyrA gene might give an estimate on the level of FQ-resistance in MDR-TB isolates from the different study sites. The frequency found differed considerably between these, with the highest frequency of FQ-resistance-related mutations seen in Belarus and Romania, from where 40% and 35% of the strains had detectable gyrA mutations. In contrast, such mutations were absent or rare in isolates from Honduras, Iran/Iraq and Uganda.
This finding reflects the more severe problem with FQ-resistance, and thus most likely also with XDR-TB, in East Europe than in the other sites.
An interesting gyrA mutation pattern among the Ugandan isolates was observed. The mutation Thr80Ala seen in this study has been previously reported from African clinical isolates  and seems to be an allelic variability marker, not conferring resistance to FQ . However, when this mutation occurs simultaneously with a well-known FQ-resistance-related mutation, the isolates are hypersusceptible to FQ . In this study, one Ugandan ofloxacin-susceptible isolate with the genotype Thr80Ala+Asp94Gly was seen. In a recent systematic review, it was postulated that the above-mentioned pattern might be due to a misclassification of the strains or due to the presence of a mixture of two different strains . Further studies on clinical isolates harboring this double mutation might clarify whether or not there are other susceptibility mechanisms involved in the mutation profile, as well as its geographical distribution and possible implications for therapy and on transmission.
The distribution of isolates belonging to the different PGGs may also be used as an indicator of the epidemiological trends in our study settings. The predominance of PGG1 isolates in China and Iran reflects the high prevalence in these countries of ancient M. tuberculosis lineages, such as Beijing  and Central Asian (CAS) . In Romania and Belarus, mainly PGG 2 and 3 isolates were observed combined with a less diverse mutation profile. This might indicate that modern M. tuberculosis lineages, like the Latin American Mediterranean (LAM) and T genotypes, are causing the clonal spread of MDR and pre-XDR isolates. More in-depth, prospective epidemiological studies in these settings are needed to understand the role of non-Beijing genotypes in the occurrence of M/XDR-TB.
A theoretical comparison of these findings with a commercially available rapid molecular test, the line probe assay (LPA) also highlights the importance of knowing the prevalence and distribution of mutations related to resistance before implementing a new test in any specific setting. If the Genotype® MTBDRplus (Hain Lifescience, Nehren, Germany)  would have been used, 97% of the katG/mabA-inhA mutants and 100% of the rpoB mutants would have been correctly detected. Thus, the overall test sensitivity would have been very good, but when site-by-site comparisons are done, only 65% and 75% of the INH-resistant isolates from Iran and Honduras, respectively, would have been identified as resistant. Similarly, the Genotype® MTBDRsl (Hain Lifescience, Nehren, Germany)  would have been able to detect the fluoroquinolone-resistance-related mutations owing to its high sensitivity for the detection of fluoroquinolone resistance, as it has been reported recently .
| Conclusion|| |
Knowledge of the prevalence of geographic-specific mutations can allow the development of in-house, PCR-based methods for targeting mutations relevant in a specific setting. Since there are clear geographical differences in the presence and proportion of resistance-related mutations, it is crucial to include enough drug-resistant clinical isolates from various parts of the world when new diagnostic tools aimed at global implementation are developed and evaluated.
| Conflict of interest|| |
There are no conflicts of interest.
| Acknowledgments|| |
This work had financial support from the Swedish International Development Cooperation Agency (Sida) and the EC projects FP7-HEALTH-2007-A-201690 (FAST-XDR-DETECT) and FP7-HEALTH-2007-B-223681 (TB PAN-NET).
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[Table 1], [Table 2], [Table 3], [Table 4]
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