Multi-drug resistant gene mutation analysis in Mycobacterium tuberculosis by molecular techniques
-
Monika Sultana
,
Mohammad Mamun Alam
,
Somen Kumar Mistri
,
S. M. Mostafa Kamal
,
Chowdhury Rafiqul Ahsan
,
Mahmuda Yasmin
Abstract
Background and Objectives: Rifampicin (RIF) and isoniazid (INH), two most potent antibiotics, are prescribed to cure tuberculosis. Mycobacterium tuberculosis, the causative agent of multidrug-resistant tuberculosis (MDR-TB), is resistant to these first-line drugs. Here, two molecular techniques were demonstrated such as PCR sequencing-based and GeneXpert assay for rapidly identifying MDR-TB.
Materials and Methods: Pulmonary samples (sputum) were collected from 55 MDR-TB suspected patients from the National Tuberculosis Reference Laboratory (NTRL), Dhaka where the research work was partially accomplished and continued in the department of Microbiology, University of Dhaka, Bangladesh. We strived for sequencing technique as well as GeneXpert assay to identify mutations in rpoB and katG genes in MTB strains and sputum directly. Culture-based drug susceptibility testing (DST) was performed to measure the efficacy of the molecular methods employed.
Results: When analyzed, rpoB gene mutations at codons 531 (54.54%), 526 (14.54%), and 516 (10.91%) were found by sequencing in 80% of the samples. Nucleotide substitution at katG315 (AGC→ACC) was spotted in 16 (76.19%) out of 21 samples. When comparing the sequencing results with DST, sensitivity and specificity were investigated to determine drug-resistance (rifampicin-resistance were 98 and 100% whereas isoniazid-resistance were 94 and 100% respectively). Additionally, as a point of comparison with DST, only 85.45% of RIF mono-resistant TB cases were accurately evaluated by the GeneXpert assay.
Conclusion: This research supports the adoption of PCR sequencing approach as an efficient tool in detecting MDR-TB, counting the higher sensitivity and specificity as well as the short period to produce the results.
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26. Wang S, Zhao B, Song Y, Zhou Y, Pang Y, Ou X, et al. Molecular characterization of the rpoB gene mutations of Mycobacterium tuberculosis isolated from China. J Tuberc Res 2013; 1: 1-8.
27. Su F, Cao L, Ren X, Hu J, Wang X, Fu Y, et al. RpoB Gene Mutation characteristics of Rifampicin-resistant tuberculosis in Anqing, China. Jundishapur J Microbiol 2022; 15(9): e127306.
28. Mani C, Selvakumar N, Narayanan S, Narayanan PR. Mutations in the rpoB gene of multidrug-resistant Mycobacterium tuberculosis clinical isolates from India. J Clin Microbiol 2001; 39: 2987-2990.
29. Valim AR, Rossetti ML, Ribeiro MO, Zaha A. Mutations in the rpoB gene of multidrug-resistant Mycobacterium tuberculosis isolates from Brazil. J Clin Microbiol 2000; 38: 3119-3122.
30. Cavusoglu C, Hilmioglu S, Guneri S, Bilgic A. Characterization of rpoB mutations in rifampin-resistant clinical isolates of Mycobacterium tuberculosis from Turkey by DNA sequencing and line probe assay. J Clin Microbiol 2002; 40: 4435-4438.
31. Thirumurugan R, Kathirvel M, Vallayyachari K, Surendar K, Samrot AV, Muthaiah M. Molecular analysis of rpoB gene mutations in rifampicin resistant Mycobacterium tuberculosis isolates by multiple allele specific polymerase chain reaction in Puducherry, South India. J Infect Public Health 2015; 8: 619-625.
32. Bártfai Z, Somoskövi A, Ködmön C, Szabó N, Puskás E, Kosztolányi L, et al. Molecular characterization of rifampin-resistant isolates of Mycobacterium tuberculosis from Hungary by DNA sequencing and the line probe assay. J Clin Microbiol 2001; 39: 3736-3739.
33. Zenteno-Cuevas R, Zenteno JC, Cuellar A, Cuevas B, Sampieri CL, Riviera JE, et al. Mutations in rpoB and katG genes in Mycobacterium isolates from the Southeast of Mexico. Mem Inst Oswaldo Cruz 2009; 104: 468-472.
34. Sinha P, Srivastava GN, Tripathi R, Mishra MN, Anupurba S. Detection of mutations in the rpoB gene of rifampicin-resistant Mycobacterium tuberculosis strains inhibiting wild type probe hybridization in the MTBDR plus assay by DNA sequencing directly from clinical specimens. BMC Microbiol 2020; 20: 284.
35. Uddin MKM, Rahman A, Ather MF, Ahmed T, Rahman SMM, Ahmed S, et al. Distribution and frequency of rpoB mutations detected by Xpert MTB/RIF assay among Beijing and non-Beijing rifampicin resistant Mycobacterium tuberculosis isolates in Bangladesh. Infect Drug Resist 2020; 13: 789-797.
36. Crudu V, Stratan E, Romancenco E, Allerheiligen V, Hillemann A, Moraru N. First evaluation of an improved assay for molecular genetic detection of tuberculosis as well as rifampin and isoniazid resistances. J Clin Microbiol 2012; 50: 1264-1269.
37. Dymova MA, Liashenko OO, Poteiko PI, Krutko VS, Khrapov EA, Filipenko ML. Genetic variation of Mycobacterium tuberculosis circulating in Kharkiv Oblast, Ukraine. BMC Infect Dis 2011; 11: 77.
38. Polu GP, Mohammad Shaik J, Kota NMK, Karumanchi D, Allam US. Analysis of drug resistance mutations in pulmonary Mycobacterium tuberculosis isolates in the Southern coastal region of Andhra Pradesh, India. Braz J Infect Dis 2019; 23: 281-290.
39. Yue J, Shi W, Xie J, Li Y, Zeng E, Wang H. Mutations in the rpoB gene of multidrug-resistant Mycobacterium tuberculosis isolates from China. J Clin Microbiol 2003; 41: 2209-2212.
40. Thwe EP, Namwat W, Pinlaor P, Rueangsak K, Sangka A. Novel mutations detected from drug resistant Mycobacterium tuberculosis isolated from North East of Thailand. World J Microbiol Biotechnol 2021; 37: 194.
41. Hillemann D, Weizenegger M, Kubica T, Richter E, Niemann S. Use of the genotype MTBDR assay for rapid detection of rifampin and isoniazid resistance in Mycobacterium tuberculosis complex isolates. J Clin Microbiol 2005; 43: 3699-3703.
42. Ocheretina O, Escuyer VE, Mabou MM, Royal-Mardi G, Collins S, Vilbrun SC, et al. Correlation between genotypic and phenotypic testing for resistance to rifampin in Mycobacterium tuberculosis clinical isolates in Haiti: investigation of cases with discrepant susceptibility results. PLoS One 2014; 9(3): e90569.
43. Unissa AN, Doss C GP, Kumar T, Sukumar S, Lakshmi AR, Hanna LE. Significance of catalase-peroxidase (KatG) mutations in mediating isoniazid resistance in clinical strains of Mycobacterium tuberculosis. J Glob Antimicrob Resist 2018; 15: 111-120.
44. Herrera L, Valverde A, Saiz P, Sáez-Nieto JA, Portero JL, Jiménez MS. Molecular characterization of isoniazid-resistant Mycobacterium tuberculosis clinical strains isolated in the Philippines. Int J Antimicrob Agents 2004; 23: 572-576.
45. Aktas E, Durmaz R, Yang D, Yang Z. Molecular characterization of isoniazid and rifampin resistance of Mycobacterium tuberculosis clinical isolates from Malatya, Turkey. Microb Drug Resist 2005; 11: 94-99.
46. Reta MA, Alemnew B, Abate BB, Fourie PB. Prevalence of drug resistance-conferring mutations associated with isoniazid- and rifampicin-resistant Mycobacterium tuberculosis in Ethiopia: a systematic review and meta-analysis. J Glob Antimicrob Resist 2021; 26: 207-218.
47. Pereira C, Larsson J, Hjort K, Elf J, Andersson DI. The highly dynamic nature of bacterial heteroresistance impairs its clinical detection. Commun Biol 2021; 4: 521.
48. Teo J, Jureen R, Chiang D, Chan D, Lin R. Comparison of two nucleic acid amplification assays, the Xpert MTB/RIF assay and the amplified Mycobacterium tuberculosis direct assay, for detection of Mycobacterium tuberculosis in respiratory and non-respiratory specimens. J Clin Microbiol 2011; 49: 3659-3662.
49. Hillemann D, Rüsch-Gerdes S, Boehme C, Richter E. Rapid molecular detection of extrapulmonary tuberculosis by the automated GeneXpert MTB/RIF system. J Clin Microbiol 2011; 49: 1202-1205.
50. Zetola NM, Shin SS, Tumedi KA, Moeti K, Ncube R, Nicol M, et al. Mixed Mycobacterium tuberculosis complex infections and false-negative results for rifampin resistance by GeneXpert MTB/RIF are associated with poor clinical outcomes. J Clin Microbiol 2014; 52: 2422-2429.
2. Noor R, Akhter S, Rahman F, Munshi SK, Kamal SM, Feroz F. requency of extensively drug-resistant tuberculosis (XDR-TB) among re-treatment cases in NIDCH, Dhaka, Bangladesh. J Infect Chemother 2013; 19: 243-248.
3. Herrera-León L, Molina T, Saíz P, Sáez-Nieto JA, Jiménez MS. New multiplex PCR for rapid detection of isoniazid-resistant Mycobacterium tuberculosis clinical isolates. Antimicrob Agents Chemother 2005; 49: 144-147.
4. Seung KJ, Keshavjee S, Rich ML. Multidrug-resistant tuberculosis and extensively drug-resistant tuberculosis. Cold Spring Harb Perspect Med 2015; 5: a017863.
5. Somoskovi A, Parsons LM, Salfinger M. The molecular basis of resistance to isoniazid, rifampin, and pyrazinamide in Mycobacterium tuberculosis. Respir Res 2001; 2: 164-168.
6. Zaw MT, Emran NA, Lin Z. Mutations inside rifampicin-resistance determining region of rpoB gene associated with rifampicin-resistance in Mycobacterium tuberculosis. J Infect Public Health 2018; 11: 605-610.
7. Cade CE, Dlouhy AC, Medzihradszky KF, Salas-Castillo SP, Ghiladi RA. Isoniazid-resistance conferring mutations in Mycobacterium tuberculosis KatG: catalase, peroxidase, and INH-NADH adduct formation activities. Protein Sci 2010; 19: 458-474.
8. Aurin TH, Munshi SK, Kamal SM, Rahman MM, Hossain MS, Marma T, et al. Molecular approaches for detection of the multi-drug resistant tuberculosis (MDR-TB) in Bangladesh. PLoS One 2014; 9(6): e99810.
9. Islam S, Rahman F, Saurab KM, Ahmed J, Kamal SMM, Noor R. Use of fluorescein diacetate (FDA) staining to detect viable Mycobacterium tuberculosis. Bangladesh J Med Sci 2012; 11: 322-330.
10. Munshi SK, Rahman F, Mostofa Kamal SM, Noor R. Comparison among different diagnostic methods used for the detection of extra-pulmonary TB in Bangladesh. Int J Mycobacteriol 2012; 1: 190-195.
11. Neonakis IK, Gitti Z, Krambovitis E, Spandidos DA. Molecular diagnostic tools in mycobacteriology. J Microbiol Methods 2008; 75: 1-11.
12. Li Z. The value of GeneXpert MTB/RIF for detection in tuberculosis: a bibliometrics-based analysis and review. J Anal Methods Chem 2022; 2022: 2915018.
13. Xpert MTB/RIF implementation manual Technical and operational ’how-to’: practical considerations. World Health Organization; 2014.
14. Ardito F, Posteraro B, Sanguinetti M, Zanetti S, Fadda G. Evaluation of BACTEC Mycobacteria Growth Indicator Tube (MGIT 960) automated system for drug susceptibility testing of Mycobacterium tuberculosis. J Clin Microbiol 2001; 39: 4440-4444.
15. Training Manual for Mycobacterium tuberculosis Culture & Drug susceptibility testing, Central TB Division, Directorate General of Health Services, Ministry of Health and Family Welfare, Nirman Bhawan, New Delhi 110011. Revised National TB Control Programme, 2009.
16. Medical microbiology – diagnosis of tuberculosis – Part 8: methods for the determination of susceptibility of tubercle bacilli to chemotherapeutic agents; text in German and English (2009).
17. Mistri SK, Sultana M, Kamal SM, Alam MM, Irin F, Nessa J, et al. Evaluation of efficiency of nested multiplex allele-specific PCR assay for detection of multidrug resistant tuberculosis directly from sputum samples. Lett Appl Microbiol 2016; 62: 411-418.
18. Rimek D, Tyagi S, Kappe R. Performance of an IS6110-based PCR assay and the COBAS AMPLICOR MTB PCR system for detection of Mycobacterium tuberculosis complex DNA in human lymph node samples. J Clin Microbiol 2002; 40: 3089-3092.
19. Sachse K, Frey J. PCR detection of microbial pathogens. Introduction. Methods Mol Biol 2003; 216: v-vi.
20. Sekiguchi J, Miyoshi-Akiyama T, Augustynowicz-Kopeć E, Zwolska Z, Kirikae F, Toyota E, et al. Detection of multidrug resistance in Mycobacterium tuberculosis. J Clin Microbiol 2007; 45: 179-192.
21. Chia BS, Lanzas F, Rifat D, Herrera A, Kim EY, Sailer C, et al. Use of multiplex allele-specific polymerase chain reaction (MAS-PCR) to detect multidrug-resistant tuberculosis in Panama. PLoS One 2012; 7(7): e40456.
22. Tamura K, Stecher G, Peterson D, Filipski A, Kumar S. MEGA6: Molecular evolutionary genetics analysis version 6.0. Mol Biol Evol 2013; 30: 2725-2729.
23. Marahatta SB, Gautam S, Dhital S, Pote N, Jha AK, Mahato R, et al. KatG (SER 315 THR) gene mutation in isoniazid resistant Mycobacterium tuberculosis. Kathmandu Univ Med J (KUMJ) 2011; 9: 19-23.
24. Lempens P, Meehan CJ, Vandelannoote K, Fissette K, de Rijk P, Van Deun A, et al. Isoniazid resistance levels of Mycobacterium tuberculosis can largely be predicted by high-confidence resistance-conferring mutations. Sci Rep 2018; 8: 3246.
25. Mokrousov I, Otten T, Vyshnevskiy B, Narvskaya O. Allele-specific rpoB PCR assays for detection of rifampin-resistant Mycobacterium tuberculosis in sputum smears. Antimicrob Agents Chemother 2003; 47: 2231-2235.
26. Wang S, Zhao B, Song Y, Zhou Y, Pang Y, Ou X, et al. Molecular characterization of the rpoB gene mutations of Mycobacterium tuberculosis isolated from China. J Tuberc Res 2013; 1: 1-8.
27. Su F, Cao L, Ren X, Hu J, Wang X, Fu Y, et al. RpoB Gene Mutation characteristics of Rifampicin-resistant tuberculosis in Anqing, China. Jundishapur J Microbiol 2022; 15(9): e127306.
28. Mani C, Selvakumar N, Narayanan S, Narayanan PR. Mutations in the rpoB gene of multidrug-resistant Mycobacterium tuberculosis clinical isolates from India. J Clin Microbiol 2001; 39: 2987-2990.
29. Valim AR, Rossetti ML, Ribeiro MO, Zaha A. Mutations in the rpoB gene of multidrug-resistant Mycobacterium tuberculosis isolates from Brazil. J Clin Microbiol 2000; 38: 3119-3122.
30. Cavusoglu C, Hilmioglu S, Guneri S, Bilgic A. Characterization of rpoB mutations in rifampin-resistant clinical isolates of Mycobacterium tuberculosis from Turkey by DNA sequencing and line probe assay. J Clin Microbiol 2002; 40: 4435-4438.
31. Thirumurugan R, Kathirvel M, Vallayyachari K, Surendar K, Samrot AV, Muthaiah M. Molecular analysis of rpoB gene mutations in rifampicin resistant Mycobacterium tuberculosis isolates by multiple allele specific polymerase chain reaction in Puducherry, South India. J Infect Public Health 2015; 8: 619-625.
32. Bártfai Z, Somoskövi A, Ködmön C, Szabó N, Puskás E, Kosztolányi L, et al. Molecular characterization of rifampin-resistant isolates of Mycobacterium tuberculosis from Hungary by DNA sequencing and the line probe assay. J Clin Microbiol 2001; 39: 3736-3739.
33. Zenteno-Cuevas R, Zenteno JC, Cuellar A, Cuevas B, Sampieri CL, Riviera JE, et al. Mutations in rpoB and katG genes in Mycobacterium isolates from the Southeast of Mexico. Mem Inst Oswaldo Cruz 2009; 104: 468-472.
34. Sinha P, Srivastava GN, Tripathi R, Mishra MN, Anupurba S. Detection of mutations in the rpoB gene of rifampicin-resistant Mycobacterium tuberculosis strains inhibiting wild type probe hybridization in the MTBDR plus assay by DNA sequencing directly from clinical specimens. BMC Microbiol 2020; 20: 284.
35. Uddin MKM, Rahman A, Ather MF, Ahmed T, Rahman SMM, Ahmed S, et al. Distribution and frequency of rpoB mutations detected by Xpert MTB/RIF assay among Beijing and non-Beijing rifampicin resistant Mycobacterium tuberculosis isolates in Bangladesh. Infect Drug Resist 2020; 13: 789-797.
36. Crudu V, Stratan E, Romancenco E, Allerheiligen V, Hillemann A, Moraru N. First evaluation of an improved assay for molecular genetic detection of tuberculosis as well as rifampin and isoniazid resistances. J Clin Microbiol 2012; 50: 1264-1269.
37. Dymova MA, Liashenko OO, Poteiko PI, Krutko VS, Khrapov EA, Filipenko ML. Genetic variation of Mycobacterium tuberculosis circulating in Kharkiv Oblast, Ukraine. BMC Infect Dis 2011; 11: 77.
38. Polu GP, Mohammad Shaik J, Kota NMK, Karumanchi D, Allam US. Analysis of drug resistance mutations in pulmonary Mycobacterium tuberculosis isolates in the Southern coastal region of Andhra Pradesh, India. Braz J Infect Dis 2019; 23: 281-290.
39. Yue J, Shi W, Xie J, Li Y, Zeng E, Wang H. Mutations in the rpoB gene of multidrug-resistant Mycobacterium tuberculosis isolates from China. J Clin Microbiol 2003; 41: 2209-2212.
40. Thwe EP, Namwat W, Pinlaor P, Rueangsak K, Sangka A. Novel mutations detected from drug resistant Mycobacterium tuberculosis isolated from North East of Thailand. World J Microbiol Biotechnol 2021; 37: 194.
41. Hillemann D, Weizenegger M, Kubica T, Richter E, Niemann S. Use of the genotype MTBDR assay for rapid detection of rifampin and isoniazid resistance in Mycobacterium tuberculosis complex isolates. J Clin Microbiol 2005; 43: 3699-3703.
42. Ocheretina O, Escuyer VE, Mabou MM, Royal-Mardi G, Collins S, Vilbrun SC, et al. Correlation between genotypic and phenotypic testing for resistance to rifampin in Mycobacterium tuberculosis clinical isolates in Haiti: investigation of cases with discrepant susceptibility results. PLoS One 2014; 9(3): e90569.
43. Unissa AN, Doss C GP, Kumar T, Sukumar S, Lakshmi AR, Hanna LE. Significance of catalase-peroxidase (KatG) mutations in mediating isoniazid resistance in clinical strains of Mycobacterium tuberculosis. J Glob Antimicrob Resist 2018; 15: 111-120.
44. Herrera L, Valverde A, Saiz P, Sáez-Nieto JA, Portero JL, Jiménez MS. Molecular characterization of isoniazid-resistant Mycobacterium tuberculosis clinical strains isolated in the Philippines. Int J Antimicrob Agents 2004; 23: 572-576.
45. Aktas E, Durmaz R, Yang D, Yang Z. Molecular characterization of isoniazid and rifampin resistance of Mycobacterium tuberculosis clinical isolates from Malatya, Turkey. Microb Drug Resist 2005; 11: 94-99.
46. Reta MA, Alemnew B, Abate BB, Fourie PB. Prevalence of drug resistance-conferring mutations associated with isoniazid- and rifampicin-resistant Mycobacterium tuberculosis in Ethiopia: a systematic review and meta-analysis. J Glob Antimicrob Resist 2021; 26: 207-218.
47. Pereira C, Larsson J, Hjort K, Elf J, Andersson DI. The highly dynamic nature of bacterial heteroresistance impairs its clinical detection. Commun Biol 2021; 4: 521.
48. Teo J, Jureen R, Chiang D, Chan D, Lin R. Comparison of two nucleic acid amplification assays, the Xpert MTB/RIF assay and the amplified Mycobacterium tuberculosis direct assay, for detection of Mycobacterium tuberculosis in respiratory and non-respiratory specimens. J Clin Microbiol 2011; 49: 3659-3662.
49. Hillemann D, Rüsch-Gerdes S, Boehme C, Richter E. Rapid molecular detection of extrapulmonary tuberculosis by the automated GeneXpert MTB/RIF system. J Clin Microbiol 2011; 49: 1202-1205.
50. Zetola NM, Shin SS, Tumedi KA, Moeti K, Ncube R, Nicol M, et al. Mixed Mycobacterium tuberculosis complex infections and false-negative results for rifampin resistance by GeneXpert MTB/RIF are associated with poor clinical outcomes. J Clin Microbiol 2014; 52: 2422-2429.
| Files | ||
| Issue | Vol 16 No 4 (2024) | |
| Section | Original Article(s) | |
| DOI | https://doi.org/10.18502/ijm.v16i4.16304 | |
| Keywords | ||
| Drug susceptibility testing; GeneXpert assay; Multidrug-resistant tuberculosis; Multidrug-resistant; Mycobacteria; Pulmonary tuberculosis | ||
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How to Cite
1.
Sultana M, Alam M, Mistri S, Kamal SM, Ahsan C, Yasmin M. Multi-drug resistant gene mutation analysis in Mycobacterium tuberculosis by molecular techniques. Iran J Microbiol. 2024;16(4):459-469.
