Abstract
Our population-based study of the Mycobacterium tuberculosis Beijing family examined the frequency of occurrence of each sublineage of this family, classified by using 10 synonymous single-nucleotide polymorphisms. The results revealed the overabundance of two evolutionary sublineages in a population of multidrug-resistant and extensively drug-resistant tuberculosis bacteria.
Mycobacterium tuberculosis Beijing family strains are suspected to be an evolving lineage of M. tuberculosis that has acquired the advantage of drug resistance (1, 8, 13, 26). However, the association between this genotype and drug resistance varies in different countries (2, 7, 26). This may be due to heterogeneity in the fitness of the sublineages of the Beijing family and to the different proportions of these sublineages in local populations (6, 9, 15, 23). To determine whether certain sublineages are associated with multidrug-resistant (MDR) and extensively drug-resistant (XDR) tuberculosis, the population structure of the Beijing strains was analyzed, based on 10 synonymous single-nucleotide polymorphisms (sSNPs) (5, 9) in pandrug-sensitive (DS), MDR, and XDR strains.
Two hundred eighty-five Beijing family strains were obtained from individual patients with pulmonary tuberculosis (TB) at the Kinki-chuo Chest Medical Center. All the patients in this study were human immunodeficiency virus negative, and most of them were residents of the Kinki area of Japan. Of the 285 strains, 189 DS strains were collected between 1 January 2003 and 31 August 2003, and 96 MDR strains (including 47 XDR strains) were collected between 1 January 2001 and 31 December 2006. These strains were from all of the DS, MDR, and XDR-TB patients with Beijing strains in this hospital during the strain collection periods except for one MDR patient.
The Beijing family strains were defined by spoligotyping (12). The strains were analyzed for drug susceptibility by using the simplified proportion method (22). All 96 MDR strains were analyzed for the presence of mutations in the rifampin resistance-determining region (RRDR) (25) and in katG codon 315 (29). Subdivisions within the Beijing family were characterized on the basis of sSNPs at 10 chromosomal positions (5, 9). In addition, the IS6110 insertion in the NTF regions (19), the presence or absence of three large sequence polymorphisms (RD181, RD150, and RD142) (27), and three nonsynonymous SNPs in putative repair genes (mutT2, mutT4, and ogt [codon 37]) (21) were analyzed. All strains were subjected to Supply's optimized 15-locus variable number of tandem repeats (15-MIRU-VNTR) analysis (24) to detect probable epidemiological linkage among the patients (see Table S1 in the supplemental material).
A total of eight independently evolving Beijing sublineages that corresponded to ancient sublineages (ST11, ST26, ST3, ST25, ST19 and newly assigned STK in this study, possessing an intact NTF region) and modern sublineages (ST10 and ST22, possessing an IS6110 insertion on the right side of the NTF region) were identified in our population (17, 18) (Table 1). The population structures based on the numbers of patients demonstrated that two sublineages, ST26 (RD181+) and ST3 (RD181−), were significantly overrepresented in the population of MDR/XDR strains compared with their numbers in the population of DS strains; however, the ST19 sublineage was significantly underrepresented in the MDR/XDR populations (Table 2). The age, gender, and human immunodeficiency virus status of the patients did not account for such differences between the DS and MDR/XDR populations (Table 2).
TABLE 1.
Distribution of drug resistance and various genetic characteristics of each sublineage
| Beijing sublineagea | Allele in indicated SNP position of H37Rv:
|
No. (%) of isolates of indicated strain:
|
IS6110 insertion in the NTF region | Point mutations in indicated putative repair genee:
|
Presence or absence of indicated large sequence polymorphismf:
|
|||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| 797736 | 909166 | 1477596 | 1548149 | 1692069 | 1892017 | 2376135 | 2532616 | 2825581 | 4137829 | DS-TB | MDR-TB | XDR-TB | mutT2 | mutT4 | ogt (codon 37) | RD181 | RD150 | RD142 | ||
| ST11 | C | C | C | G | A | T | A | G | T | C | 1 (0.5) | 0 (0) | 0 (0) | None | WT | WT | WT | + | + | + |
| ST26 | C | T | C | G | A | T | A | G | T | C | 10 (5.3) | 21 (21.9) | 17 (36.2) | None | WT | WT | WT | + | + | + |
| Noneb | T | T | C | G | A | T | A | G | G | C | 30 (16.0) | 8 (8.2) | 2 (4.3) | None | WT | WT | WT | - | + | + |
| ST3 | T | C | C | G | A | T | A | G | G | C | 44 (23.4) | 34 (35.1) | 20 (42.6) | None | WT | WT | WT | - | + | + |
| ST25 | T | C | C | G | A | C | A | G | G | T | 3 (1.6) | 1 (1.0) | 0 (0) | None | WT | MT | MT | - | + | + |
| ST19 | T | T | C | G | A | C | A | G | G | T | 63 (33.5) | 14 (14.4) | 3 (6.4) | None | WT | MT | MTc | - | + | + |
| ST10 | T | T | T | G | A | C | A | G | G | T | 29 (15.4) | 8 (8.2) | 1 (2.1) | NTF::IS6110 | MT | MT | WT | - | +d | + |
| ST22 | T | T | T | G | A | C | G | A | G | T | 9 (4.8) | 10 (10.3) | 4 (8.5) | NTF::IS6110 | MT | MT | WT | - | + | + |
ST designations from reference 5.
New ST, STK, assigned in this study.
Nine DS-TB strains and one MDR-TB strain possessed the wild type.
Two strains exhibiting ST10 had the RD150 deletion.
WT, wild type; MT, mutation.
+, presence of large sequence polymorphism; −, absence of large sequence polymorphism.
TABLE 2.
Epidemiological, clinical, and genotypic data from DS-TB, MDR-TB, and XDR-TB isolates
| Drug sensitivity groupa and Beijing sublineage | Epidemiological/clinical information
|
Genotypic information as determined by VNTR analysis
|
|||||||
|---|---|---|---|---|---|---|---|---|---|
| Total no. (%) of patients | P valueb | No. (%) male | Avg age (yrs) | No. (%) of new cases | Total no. (%) of genotypes by VNTR analysis | P valuec | No. of clusters | No. (%) of cases in cluster | |
| DS | |||||||||
| ST11 | 1 (0.5) | 1 (100) | 54 | 1 (100) | 1 (0.8) | 0 | 0 (0) | ||
| ST26 | 10 (5.3) | 6 (60.0) | 56.6 | 8 (80.0) | 9 (7.3) | 1 | 2 (22.2) | ||
| STK | 30 (15.9) | 22 (73.3) | 58.8 | 23 (76.7) | 27 (22.0) | 3 | 6 (20.0) | ||
| ST3 | 44 (23.3) | 33 (75.0) | 57.2 | 37 (84.1) | 26 (21.1) | 10 | 28 (63.6) | ||
| ST25 | 3 (1.6) | 3 (100) | 61.3 | 2 (66.7) | 2 (1.6) | 1 | 2 (66.7) | ||
| ST19 | 63 (33.3) | 48 (76.2) | 59.3 | 52 (82.5) | 31 (25.2) | 6 | 38 (60.3) | ||
| ST10 | 29 (15.3) | 23 (79.3) | 58.2 | 22 (75.9) | 21 (17.1) | 4 | 12 (41.4) | ||
| ST22 | 9 (4.8) | 5 (55.6) | 54.2 | 9 (100) | 6 (4.9) | 1 | 4 (44.4) | ||
| MDR | |||||||||
| ST11 | 0 (0) | ||||||||
| ST26 | 21 (21.9) | <0.01 | 18 (85.7) | 53.8 | 4 (19.0) | 10 (18.2) | 0.028 | 3 | 14 (63.6) |
| STK | 8 (8.3) | 0.056 | 6 (75.0) | 59.1 | 2 (25.0) | 8 (14.6) | 0.173 | 0 | 0 (0) |
| ST3 | 34 (35.4) | 0.021 | 24 (70.6) | 58.8 | 5 (14.7) | 18 (32.8) | 0.071 | 6 | 22 (64.7) |
| ST25 | 1 (1.0) | 0.563 | 1 (100) | 50 | 1 (100) | 1 (1.8) | 0.705 | 0 | 0 (0) |
| ST19 | 14 (14.6) | <0.01 | 10 (71.4) | 54.9 | 4 (28.6) | 8 (14.6) | 0.082 | 2 | 8 (57.1) |
| ST10 | 8 (8.3) | 0.07 | 5 (62.5) | 44.8 | 5 (62.5) | 6 (10.9) | 0.203 | 2 | 4 (50) |
| ST22 | 10 (10.4) | 0.059 | 9 (90) | 55.8 | 2 (20.0) | 4 (7.3) | 0.387 | 3 | 9 (90) |
| XDR | |||||||||
| ST11 | 0 (0) | ||||||||
| ST26 | 17 (36.2) | <0.01 | 14 (82.4) | 52.4 | 3 (17.6) | 7 (29.2) | <0.01 | 2 | 12 (70.6) |
| STK | 2 (4.3) | 0.033 | 2 (100) | 68 | 0 (0) | 2 (8.3) | 0.105 | 0 | 0 |
| ST3 | 20 (42.6) | <0.01 | 13 (65.0) | 58.2 | 3 (15.0) | 10 (41.7) | 0.03 | 3 | 13 (65.0) |
| ST25 | 0 (0) | ||||||||
| ST19 | 3 (6.4) | <0.01 | 2 (66.7) | 59.3 | 2 (66.7) | 2 (8.3) | 0.061 | 1 | 2 (66.7) |
| ST10 | 1 (2.1) | 0.014 | 1 (100) | 52 | 0 (0) | 1 (4.2) | 0.095 | 0 | 0 (0) |
| ST22 | 4 (8.5) | 0.257 | 3 (75.0) | 46.5 | 1 (25.0) | 2 (8.3) | 0.425 | 1 | 3 (75.0) |
There were 189 DS-TB, 96 MDR-TB, and 47 XDR-TB isolates.
P value of Z test for proportion between DS versus MDR and DS versus XDR patients.
P value of Z test for proportion between DS versus MDR and DS versus XDR genotypes.
The MDR/XDR populations in this study mostly comprised previously treated patients (Table 2). This might imply that clonal evolution within a patient is a driving force for acquiring MDR/XDR. In order to clarify the contribution of clonal evolution, excluding clonal expansion (human-to-human transmission), on the overabundance of ST26 and ST3, the population structures based on the genotypes determined by 15-MIRU-VNTR analysis, which can discriminate epidemiologically unrelated strains as different VNTR profiles (10, 11, 28), were compared (Table 2). Genotype-based analysis demonstrated a trend similar to that observed with patient-based analysis, although there was a slight decrease in the statistical significance (Table 2). The variety of RRDR and katG 315 mutations in the strains employed in this study (Table 3; see Table S2 in the supplemental material) confirms the assumption that the strains from each sublineage evolved independently, not from an endemic MDR-TB strain. Taken together, the overrepresentation of the two sublineages could be considered reflective of the actual situation in the MDR/XDR population rather than an artifact biased by the prevalence of an endemic MDR-TB strain.
TABLE 3.
Mutations in RRDR and katG 315
| rpoB mutation(s)a | katG 315 mutationa | No. (%) of MDR-TB isolates from indicated sublineage:
|
No. (%) of XDR-TB isolates from indicated sublineage:
|
|||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| ST26 | STK | ST3 | ST25 | ST19 | ST10 | ST22 | ST26 | STK | ST3 | ST19 | ST10 | ST22 | ||
| Leu 511 Pro (CTG → CCG) | None | 1 (12.5) | ||||||||||||
| Ser 315 Thr | ||||||||||||||
| Glu 513 Lys (CAA → AAA) | None | |||||||||||||
| Ser 315 Thr | 1 (12.5) | 1 (2.9) | 1 (50) | |||||||||||
| Asp 516 Val (GAC → CTC) | None | 1 (4.8) | 3 (37.5) | 1 (2.9) | ||||||||||
| Ser 315 Thr | 1 (12.5) | 11 (32.4) | 10 (50) | |||||||||||
| Ser 522 Leu (TCG → TTG) | None | 3 (8.8) | ||||||||||||
| Ser 315 Thr | ||||||||||||||
| 525 (ACG insertion) | None | 1 (2.9) | ||||||||||||
| Ser 315 Thr | ||||||||||||||
| His 526 Ser (CAC → AGC) | None | 2 (5.9) | 4 (40) | 3 (75) | ||||||||||
| Ser 315 Thr | ||||||||||||||
| His 526 Pro (CAC → CCC) | None | 1 (2.9) | 1 (5) | |||||||||||
| Ser 315 Thr | ||||||||||||||
| His 526 Arg (CAC → CGC) | None | 2 (25) | 1 (100) | |||||||||||
| Ser 315 Thr | ||||||||||||||
| His 526 Leu (CAC → CTC) | None | 1 (4.8) | ||||||||||||
| Ser 315 Thr | ||||||||||||||
| His 526 Leu (CAC → TTG) | None | |||||||||||||
| Ser 315 Thr | 1 (12.5) | |||||||||||||
| His 526 Asp (CAC → GAC) | None | 1 (10) | ||||||||||||
| Ser 315 Thr | 1 (100) | 1 (7.1) | ||||||||||||
| His 526 Tyr (CAC → TAC) | None | 1 (12.5) | 2 (5.9) | 1 (7.1) | 1 (5) | |||||||||
| Ser 315 Asn (AGC → AAC) | 1 (2.9) | 1 (5) | ||||||||||||
| His 526 Cys (CAC → TGC) | None | |||||||||||||
| Ser 315 Thr | 1 (7.1) | |||||||||||||
| Ser 531 Leu (TCG → TTG) | None | 4 (19.0) | 1 (12.5) | 5 (14.7) | 9 (64.3) | 1 (12.5) | 4 (40) | 3 (17.6) | 1 (50) | 4 (20) | 2 (66.7) | 1 (25) | ||
| Ser 315 Thr | 14 (66.7) | 3 (8.8) | 3 (37.5) | 14 (82.4) | 1 (5) | |||||||||
| Leu 533 Pro (CTG → CCG) | None | |||||||||||||
| Ser 315 Thr | 1 (10) | |||||||||||||
| Ser 512 Ile (AGC → ATC), | None | 1 (2.9) | 1 (5) | |||||||||||
| His 526 Pro | Ser 315 Thr | |||||||||||||
| (CAC → CCC) | ||||||||||||||
| Asp 516 Glu (GAC → GAA), | None | |||||||||||||
| Ser 522 Leu (TCG → TTG) | Ser 315 Thr | 1 (2.9) | 1 (5) | |||||||||||
| Asp 516 Ala (GAC → GCC), | None | |||||||||||||
| Leu 533 Pro (CTG → CCG) | Ser 315 Thr | 1 (7.1) | 1 (33.3) | |||||||||||
| Mixed peak in 516 (CAC, GTC), 526 (CAC, CAA), 530 (CTG, ATG), 531 (TCG, TTC) | None Ser 315 Thr | 1 (2.9) | ||||||||||||
| Wild-type RRDR | None | 1 (7.1) | 1 (12.5) | |||||||||||
| Ser 315 Thr | 1 (4.8) | |||||||||||||
The mutant codon is indicated, followed by the nucleotide change.
The relatively high rate of cluster formation by the MDR/XDR strains, as observed by 15-MIRU-VNTR analysis (Table 2), suggests the occurrence of exogenous reinfection and/or transmission (clonal expansion) at a certain frequency. Due to the lack of information on patients' initially isolated strains, the inability to discriminate between clonal evolution and reinfection/transmission is a limitation of this study. Only four cases of epidemiological links were identified by tracing the patients' contacts (see Table S2 in the supplemental material).
Although we cannot rule out factors of social behavior in this study, the overrepresentation of the two sublineages in the study leads to the hypothesis that there are certain bacterial factors favoring their emergence and spread. Since the relative fitness of drug-resistant M. tuberculosis strains is considered one of the key determinants of MDR-TB burden (3, 4, 6), these sublineages may be at an advantage in acquiring drug resistance via mechanisms having a low fitness cost. To examine this possibility, we analyzed the rpoB S531L and katG S315T mutations, which are suspected to be mutations with low fitness costs. As expected, a high rate of the rpoB S531L and katG S315T mutations was observed in ST26 (85.7% and 71.4%, respectively, in MDR-TB) (Table 3). However, in ST3, the rate of katG S315T mutations was high (50% in MDR-TB), but that of rpoB S531L mutations was unexpectedly low (23.5% in MDR-TB) (Table 3). It is interesting to note that ST3 showed a variety of mutations in the RRDR regions (Table 3). Two strains demonstrated double mutations and one showed mixed peaks corresponding to wild-type and mutant genotypes in codons 516, 526, 530, and 531, which may imply the existence of subpopulations with different drug resistance alleles (20). Besides low-cost resistance mutations, compensatory mutations that ameliorate fitness costs are suggested to be important factors influencing fitness (3, 4, 6). It is possible that the ST3 sublineages are at an advantage due to the occurrence of compensatory mutations.
We also examined the appearance of missense alterations in mutT2, mutT4, and ogt, which are putative genes encoding DNA repair enzymes (21). Mutations were observed in ST25, ST19, ST10, and ST22 but not in ST11, ST26, STK, and ST3 (Table 1). Thus, our data did not demonstrate an association between the presence of mutations in these genes and MDR/XDR, while there was an association between the sSNP subclassification and the polymorphism of the genes (Table 1).
Only a few studies have investigated the association of the Beijing family with drug resistance at the sublineage level (9, 15). Compared with those of previous studies, our population is advantageous for the analysis of the ancient Beijing subgroup because of its high proportion of ancient subgroup lineages versus global dissemination of modern subgroup lineages (2, 14, 16, 17). We demonstrated that two sublineages, ST26 and ST3, which occurred with a significantly higher frequency in the MDR/XDR population than in the DS population, belong to an ancient subgroup. This finding suggests that different sublineages of the Beijing family may differ in their mechanisms of adaptation to drug selection pressures. The increasing prevalence of these sublineages would make it more difficult to control the threat posed by MDR/XDR than by those currently encountered. Therefore, greater vigilance in monitoring the occurrence of these strains is indispensable for achieving better TB control in this region.
Supplementary Material
Acknowledgments
This work was supported by grants from JSPS Grant-in-Aid for Scientific Research (A) (20249007) and the US-Japan Cooperative Medical Science Program (TB leprosy panel).
Footnotes
Published ahead of print on 11 August 2008.
Supplemental material for this article may be found at http://aac.asm.org/.
REFERENCES
- 1.Anh, D. D., M. W. Borgdorff, L. N. Van, N. T. Lan, T. van Gorkom, K. Kremer, and D. van Soolingen. 2000. Mycobacterium tuberculosis Beijing genotype emerging in Vietnam. Emerg. Infect. Dis. 6:302-305. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 2.Bifani, P. J., B. Mathema, N. E. Kurepina, and B. N. Kreiswirth. 2002. Global dissemination of the Mycobacterium tuberculosis W-Beijing family strains. Trends Microbiol. 10:45-52. [DOI] [PubMed] [Google Scholar]
- 3.Cohen, T., and M. Murray. 2004. Modeling epidemics of multidrug-resistant M. tuberculosis of heterogeneous fitness. Nat. Med. 10:1117-1121. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 4.Cohen, T., B. Sommers, and M. Murray. 2003. The effect of drug resistance on the fitness of Mycobacterium tuberculosis. Lancet Infect. Dis. 3:13-21. [DOI] [PubMed] [Google Scholar]
- 5.Filliol, I., A. S. Motiwala, M. Cavatore, W. Qi, M. H. Hazbon, M. Bobadilla del Valle, J. Fyfe, L. Garcia-Garcia, N. Rastogi, C. Sola, T. Zozio, M. I. Guerrero, C. I. Leon, J. Crabtree, S. Angiuoli, K. D. Eisenach, R. Durmaz, M. L. Joloba, A. Rendon, J. Sifuentes-Osornio, A. Ponce de Leon, M. D. Cave, R. Fleischmann, T. S. Whittam, and D. Alland. 2006. Global phylogeny of Mycobacterium tuberculosis based on single nucleotide polymorphism (SNP) analysis: insights into tuberculosis evolution, phylogenetic accuracy of other DNA fingerprinting systems, and recommendations for a minimal standard SNP set. J. Bacteriol. 188:759-772. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 6.Gagneux, S., C. D. Long, P. M. Small, T. Van, G. K. Schoolnik, and B. J. Bohannan. 2006. The competitive cost of antibiotic resistance in Mycobacterium tuberculosis. Science 312:1944-1946. [DOI] [PubMed] [Google Scholar]
- 7.Glynn, J. R., A. C. Crampin, H. Traore, M. D. Yates, F. D. Mwaungulu, B. M. Ngwira, S. D. Chaguluka, D. T. Mwafulirwa, S. Floyd, C. Murphy, F. A. Drobniewski, and P. E. Fine. 2005. Mycobacterium tuberculosis Beijing genotype, northern Malawi. Emerg. Infect. Dis. 11:150-153. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 8.Glynn, J. R., J. Whiteley, P. J. Bifani, K. Kremer, and D. van Soolingen. 2002. Worldwide occurrence of Beijing/W strains of Mycobacterium tuberculosis: a systematic review. Emerg. Infect. Dis. 8:843-849. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 9.Hanekom, M., G. D. van der Spuy, E. Streicher, S. L. Ndabambi, C. R. McEvoy, M. Kidd, N. Beyers, T. C. Victor, P. D. van Helden, and R. M. Warren. 2007. A recently evolved sublineage of the Mycobacterium tuberculosis Beijing strain family is associated with an increased ability to spread and cause disease. J. Clin. Microbiol. 45:1483-1490. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 10.Iwamoto, T., S. Yoshida, K. Suzuki, M. Tomita, R. Fujiyama, N. Tanaka, Y. Kawakami, and M. Ito. 2007. Hypervariable loci that enhance the discriminatory ability of newly proposed 15-loci and 24-loci variable-number tandem repeat typing method on Mycobacterium tuberculosis strains predominated by the Beijing family. FEMS Microbiol. Lett. 270:67-74. [DOI] [PubMed] [Google Scholar]
- 11.Jiao, W. W., I. Mokrousov, G. Z. Sun, Y. J. Guo, A. Vyazovaya, O. Narvskaya, and A. D. Shen. 2008. Evaluation of new variable-number tandem-repeat systems for typing Mycobacterium tuberculosis with Beijing genotype isolates from Beijing, China. J. Clin. Microbiol. 46:1045-1049. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 12.Kremer, K., J. R. Glynn, T. Lillebaek, S. Niemann, N. E. Kurepina, B. N. Kreiswirth, P. J. Bifani, and D. van Soolingen. 2004. Definition of the Beijing/W lineage of Mycobacterium tuberculosis on the basis of genetic markers. J. Clin. Microbiol. 42:4040-4049. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 13.Krüüner, A., S. E. Hoffner, H. Sillastu, M. Danilovits, K. Levina, S. B. Svenson, S. Ghebremichael, T. Koivula, and G. Kallenius. 2001. Spread of drug-resistant pulmonary tuberculosis in Estonia. J. Clin. Microbiol. 39:3339-3345. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 14.Kurepina, N. E., S. Sreevatsan, B. B. Plikaytis, P. J. Bifani, N. D. Connell, R. J. Donnelly, D. van Sooligen, J. M. Musser, and B. N. Kreiswirth. 1998. Characterization of the phylogenetic distribution and chromosomal insertion sites of five IS6110 elements in Mycobacterium tuberculosis: non-random integration in the dnaA-dnaN region. Tuber. Lung Dis. 79:31-42. [DOI] [PubMed] [Google Scholar]
- 15.Mokrousov, I., W. W. Jiao, G. Z. Sun, J. W. Liu, V. Valcheva, M. Li, O. Narvskaya, and A. D. Shen. 2006. Evolution of drug resistance in different sublineages of Mycobacterium tuberculosis Beijing genotype. Antimicrob. Agents Chemother. 50:2820-2823. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 16.Mokrousov, I., W. W. Jiao, V. Valcheva, A. Vyazovaya, T. Otten, H. M. Ly, N. N. Lan, E. Limeschenko, N. Markova, B. Vyshnevskiy, A. D. Shen, and O. Narvskaya. 2006. Rapid detection of the Mycobacterium tuberculosis Beijing genotype and its ancient and modern sublineages by IS6110-based inverse PCR. J. Clin. Microbiol. 44:2851-2856. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 17.Mokrousov, I., H. M. Ly, T. Otten, N. N. Lan, B. Vyshnevskyi, S. Hoffner, and O. Narvskaya. 2005. Origin and primary dispersal of the Mycobacterium tuberculosis Beijing genotype: clues from human phylogeography. Genome Res. 15:1357-1364. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 18.Mokrousov, I., O. Narvskaya, T. Otten, A. Vyazovaya, E. Limeschenko, L. Steklova, and B. Vyshnevskyi. 2002. Phylogenetic reconstruction within Mycobacterium tuberculosis Beijing genotype in northwestern Russia. Res. Microbiol. 153:629-637. [DOI] [PubMed] [Google Scholar]
- 19.Plikaytis, B. B., J. L. Marden, J. T. Crawford, C. L. Woodley, W. R. Butler, and T. M. Shinnick. 1994. Multiplex PCR assay specific for the multidrug-resistant strain W of Mycobacterium tuberculosis. J. Clin. Microbiol. 32:1542-1546. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 20.Post, F. A., P. A. Willcox, B. Mathema, L. M. Steyn, K. Shean, S. V. Ramaswamy, E. A. Graviss, E. Shashkina, B. N. Kreiswirth, and G. Kaplan. 2004. Genetic polymorphism in Mycobacterium tuberculosis isolates from patients with chronic multidrug-resistant tuberculosis. J. Infect. Dis. 190:99-106. [DOI] [PubMed] [Google Scholar]
- 21.Rad, M. E., P. Bifani, C. Martin, K. Kremer, S. Samper, J. Rauzier, B. Kreiswirth, J. Blazquez, M. Jouan, D. van Soolingen, and B. Gicquel. 2003. Mutations in putative mutator genes of Mycobacterium tuberculosis strains of the W-Beijing family. Emerg. Infect. Dis. 9:838-845. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 22.Ryoken, T. R. C. 2007. Drug-resistant Mycobacterium tuberculosis in Japan: a nationwide survey, 2002. Int. J. Tuber. Lung Dis. 11:1129-1135. [PubMed] [Google Scholar]
- 23.Strauss, O. J., R. M. Warren, A. Jordaan, E. M. Streicher, M. Hanekom, A. A. Falmer, H. Albert, A. Trollip, E. Hoosain, P. D. van Helden, and T. C. Victor. 2008. Spread of a low-fitness drug-resistant Mycobacterium tuberculosis strain in a setting of high human immunodeficiency virus prevalence. J. Clin. Microbiol. 46:1514-1516. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 24.Supply, P., C. Allix, S. Lesjean, M. Cardoso-Oelemann, S. Rusch-Gerdes, E. Willery, E. Savine, P. de Haas, H. van Deutekom, S. Roring, P. Bifani, N. Kurepina, B. Kreiswirth, C. Sola, N. Rastogi, V. Vatin, M. C. Gutierrez, M. Fauville, S. Niemann, R. Skuce, K. Kremer, C. Locht, and D. van Soolingen. 2006. Proposal for standardization of optimized mycobacterial interspersed repetitive unit-variable-number tandem repeat typing of Mycobacterium tuberculosis. J. Clin. Microbiol. 44:4498-4510. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 25.Telenti, A., P. Imboden, F. Marchesi, D. Lowrie, S. Cole, M. J. Colston, L. Matter, K. Schopfer, and T. Bodmer. 1993. Detection of rifampicin-resistance mutations in Mycobacterium tuberculosis. Lancet 341:647-650. [DOI] [PubMed] [Google Scholar]
- 26.Toungoussova, O. S., P. Sandven, A. O. Mariandyshev, N. I. Nizovtseva, G. Bjune, and D. A. Caugant. 2002. Spread of drug-resistant Mycobacterium tuberculosis strains of the Beijing genotype in the Archangel Oblast, Russia. J. Clin. Microbiol. 40:1930-1937. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 27.Tsolaki, A. G., S. Gagneux, A. S. Pym, Y. O. Goguet de la Salmoniere, B. N. Kreiswirth, D. Van Soolingen, and P. M. Small. 2005. Genomic deletions classify the Beijing/W strains as a distinct genetic lineage of Mycobacterium tuberculosis. J. Clin. Microbiol. 43:3185-3191. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 28.Yokoyama, E., K. Kishida, M. Uchimura, and S. Ichinohe. 2007. Improved differentiation of Mycobacterium tuberculosis strains, including many Beijing genotype strains, using a new combination of variable number of tandem repeats loci. Infect. Genet. Evol. 7:499-508. [DOI] [PubMed] [Google Scholar]
- 29.Zhang, Y., T. Garbe, and D. Young. 1993. Transformation with katG restores isoniazid-sensitivity in Mycobacterium tuberculosis isolates resistant to a range of drug concentrations. Mol. Microbiol. 8:521-524. [DOI] [PubMed] [Google Scholar]
Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.