Molecular mechanisms of action and resistance to the first-line drugs against Mycobacterium tuberculosis

Paper Details

Research Paper 03/05/2024
Views (429) Download (40)
current_issue_feature_image
publication_file

Molecular mechanisms of action and resistance to the first-line drugs against Mycobacterium tuberculosis

Md Zahid Hasan, Maysha Fahmeda Priota, Md Mosabbir Hossain, Md Maruf Chowdhury, Debobrata Sharma, Fateama Sikdhar, B.M. Mahmudul Hasan, Md Mahmudul Islam
Int. J. Biosci.24( 5), 38-49, May 2024.
Certificate: IJB 2024 [Generate Certificate]

Abstract

Tuberculosis, caused by the infectious pathogenic bacteria Mycobacterium tuberculosis, is one of the top 10 infectious agents (above AIDS/HIV) that cause death globally, and a large number of people contract the disease every year. Significantly, the four first-line drugs (rifampicin, isoniazid, pyrazinamide, and ethambutol) that make up the foundation of treatment regimens throughout the first six to nine months of treatment are delivered in various combinations when administering TB treatments. It is very important to continuously update information on molecular mechanisms of action and resistance to the anti-tuberculosis drugs against M. tuberculosis due the global rises in 558 000 new cases of rifampicin-resistant/ multidrug-resistant tuberculosis recently.In many countries and regions, even more severe cases of drug resistance have been documented in recent years. The aim of this review is to provide an overview of the latest report on molecular mechanisms of action and resistance to the first-line drugs against M. tuberculosis.A better knowledge of the mechanisms of action and resistance of anti-tuberculosis drugs would be very helpful for efficient tuberculosis therapy and clinical care.

VIEWS 123

Alangaden GJ, Kreiswirth BN, Aouad A, Khetarpal M, Igno FR, Moghazeh SL, Manavathu EK, Lerner SA. 1998. Mechanism of resistance to amikacin and kanamycin in Mycobacterium tuberculosis. Antimicrobial Agents and Chemotherapy 42, 1295-1297. https://doi.org/10.1128/AAC.42.5.1295.

Bakuła Z, Napiórkowska A, Bielecki J, Augustynowicz-Kopeć E, Zwolska Z, Jagielski T. 2013. Mutations in the embB gene and their association with ethambutol resistance in multidrug-resistant Mycobacterium tuberculosis clinical isolates from Poland. BioMed Research International 2013, 167954. https://doi.org/10.1155/2013/167954.

Banerjee A, Dubnau E, Quemard A, Balasubramanian V, Um KS, Wilson T, Collins D, de Lisle G, Jacobs WR. 1994. inhA, a gene encoding a target for isoniazid and ethionamide in Mycobacterium tuberculosis. Science 263, 227-230. https://doi.org/10.1126/science.8284673.

Baulard AR, Betts JC, Engohang-Ndong J, Quan S, McAdam RA, Brennan PJ, Locht C, Besra GS. 2000. Activation of the pro-drug ethionamide is regulated in mycobacteria. Journal of Biological Chemistry 275, 28326-28331. https://doi.org/10.1074/jbc.M003744200.

Boshoff HI, Warner DF, Gold B. 2023. Drug-resistant Mycobacterium tuberculosis. Frontiers in Cellular and Infection Microbiology 13, 1215294. https://doi.org/10.3389/fcimb.2023.1215294.

Bruning JB, Murillo AC, Chacon O, Barletta RG, Sacchettini JC. 2011. Structure of the Mycobacterium tuberculosis D-alanine: D-alanine ligase, a target of the antituberculosis drug D-cycloserine. Antimicrobial Agents and Chemotherapy 55, 291-301. https://doi.org/10.1128/AAC.00558-10.

Bu Q, Qiang R, Fang L, Peng X, Zhang H, Cheng H. 2023. Global trends in the incidence rates of MDR and XDR tuberculosis: findings from the global burden of disease study 2019. Frontiers in Pharmacology 14, 1156249. https://doi.org/10.3389/fphar.2023.1156249.

Caceres NE, Harris NB, Wellehan JF, Feng Z, Kapur V, Barletta RG. 1997. Overexpression of the D-alanine racemase gene confers resistance to D-cycloserine in Mycobacterium smegmatis. Journal of Bacteriology 179, 5046-5055. https://doi.org/10.1128/jb.179.16.5046-5055.1997.

Cohen KA, Stott KE, Munsamy V, Manson AL, Earl AM, Pym AS. 2020. Evidence for expanding the role of streptomycin in the management of drug-resistant Mycobacterium tuberculosis. Antimicrobial Agents and Chemotherapy 64, 10-128. https://doi.org/10.1128/AAC.00860-20.

Comas I, Borrell S, Roetzer A, Rose G, Malla B, Kato-Maeda M, Galagan J, Niemann S, Gagneux S. 2012. Whole-genome sequencing of rifampicin-resistant Mycobacterium tuberculosis strains identifies compensatory mutations in RNA polymerase genes. Nature Genetics 44, 106. https://doi.org/10.1038/ng.1038.

Dartois VA, Rubin EJ. 2022. Anti-tuberculosis treatment strategies and drug development: challenges and priorities. Nature Reviews Microbiology 20, 685-701. https://doi.org/10.1038/s41579-022-00731-y.

Dheda K, Gumbo T, Gandhi NR, Murray M, Theron G, Udwadia Z, Migliori GB, Warren R. 2014. Global control of tuberculosis: from extensively drug-resistant to untreatable tuberculosis. The lancet Respiratory Medicine 2, 321-338. https://doi.org/10.1016/S2213-2600(14)70031-1.

Farooqi JQ, Khan E, Alam SM, Ali A, Hasan Z, Hasan R. 2012. Line probe assay for detection of rifampicin and isoniazid resistant tuberculosis in Pakistan. Journal of Pakistan Medical Association 62, 767.

Fox HH. 1952. The chemical approach to the control of tuberculosis. Science 116, 129-134. https://doi.org/10.1126/science.116.3006.129.

Gandhi NR, Nunn P, Dheda K, Schaaf HS, Zignol M, Van Soolingen D, Jensen P, Bayona J. 2010. Multidrug-resistant and extensively drug-resistant tuberculosis: a threat to global control of tuberculosis. The Lancet 375, 1830-43. https://doi.org/10.1016/S0140-6736(10)60410-2.

Ginsburg AS, Woolwine SC, Hooper N, Benjamin Jr WH, Bishai WR, Dorman SE, Sterling TR. 2003. The rapid development of fluoroquinolone resistance in M. tuberculosis. New England Journal of Medicine 349, 1977-1978. https://doi.org/10.1056/NEJM200311133492023.

Hsu LY, Lai LY, Hsieh PF, Lin TL, Lin WH, Tasi HY, Lee WT, Jou R, Wang JT. 2020. Two novel katG mutations conferring isoniazid resistance in Mycobacterium tuberculosis. Frontiers in Microbiology 11, 1644. https://doi.org/10.3389/fmicb.2020.01644.

Huang H, Zhang Y, Li S, Wang J, Chen J, Pan Z, Gan H. 2018. Rifampicin resistance and multidrug-resistant tuberculosis detection using Xpert MTB/RIF in Wuhan, China: a retrospective study. Microbial Drug Resistance 24, 675-679. https://doi.org/10.1089/mdr.2017.0114.

Islam MM, Alam MS, Liu Z, Khatun MS, Yusuf B, Hameed HMA, Tian X, Chhotaray C, Basnet R, Abraha H, Zhang X, Khan SA, Fang C, Li C, Hasan S, Tan S, Zhong N, Hu J and Zhang T. 2024. Molecular mechanisms of resistance and treatment efficacy of clofazimine and bedaquiline against Mycobacterium tuberculosis. Frontiers in Medicine 10, 1304857. https://doi.org/10.3389/fmed.2023.1304857.

Jagielski T, Bakuła Z, Brzostek A, Minias A, Stachowiak R, Kalita J, Napiórkowska A, Augustynowicz-Kopeć E, Żaczek A, Vasiliauskiene E, Bielecki J. 2018. Characterization of mutations conferring resistance to rifampin in Mycobacterium tuberculosis clinical strains. Antimicrobial agents and chemotherapy 62, 10-128. https://doi.org/10.1128/AAC.01093-18.

Jia H, Xu Y, Sun Z. 2021. Analysis on Drug-Resistance-Associated Mutations among Multidrug-Resistant Mycobacterium tuberculosis Isolates in China. Antibiotics 10, 1367. https://doi.org/10.3390/antibiotics10111367.

Johansen SK, Maus CE, Plikaytis BB, Douthwaite S. 2006. Capreomycin binds across the ribosomal subunit interface using tlyA-encoded 2′-O-methylations in 16S and 23S rRNAs. Molecular Cell 23, 173-182. https://doi.org/10.1016/j.molcel.2006.05.044.

Kandler JL, Mercante AD, Dalton TL, Ezewudo MN, Cowan LS, Burns SP, Metchock B, Cegielski P, Posey JE. 2018. Validation of novel Mycobacterium tuberculosis isoniazid resistance mutations not detectable by common molecular tests. Antimicrobial Agents and Chemotherapy 62, 10-128. https://doi.org/10.1128/AAC.00974-18. 10.1128/AAC.00974-18.

Khan AS, Phelan JE, Khan MT, Ali S, Qasim M, Mohammad N, Napier G, Ahmad S, Alam J, Khattak B, Campino S. 2023. Genetic mutations underlying isoniazid-resistant Mycobacterium tuberculosis in Khyber Pakhtunkhwa, Pakistan. Tuberculosis 138, 102286. https://doi.org/10.1016/j.tube.2022.102286.

Kiepiela P, Bishop KS, Smith AN, Roux L, York DF. 2000. Genomic mutations in the katG, inhA and aphC genes are useful for the prediction of isoniazid resistance in Mycobacterium tuberculosis isolates from Kwazulu Natal, South Africa. Tubercle and Lung Disease 80, 47-56. https://doi.org/10.1054/tuld.1999.0231.

Lai C, Xu J, Tozawa Y, Okamoto-Hosoya Y, Yao X, Ochi K. 2002. Genetic and physiological characterization of rpoB mutations that activate antibiotic production in Streptomyces lividans. Microbiology 148, 3365-3373. https://doi.org/10.1099/00221287-148-11-3365.

Lei B, Wei CJ, Tu SC. 2000. Action mechanism of antitubercular isoniazid Activation by Mycobacterium tuberculosisKatG, isolation, and characterization of InhA inhibitor. Journal of Biological Chemistry 275, 2520-2526. https://doi.org/10.1074/jbc.275.4.2520.

Maus CE, Plikaytis BB, Shinnick TM. 2005. Molecular analysis of cross-resistance to capreomycin, kanamycin, amikacin, and viomycin in Mycobacterium tuberculosis. Antimicrobial Agents and Chemotherapy 49, 3192-7. https://doi.org/10.1128/AAC.49.8.3192-3197.2005.

Mdluli K, Slayden RA, Zhu Y, Ramaswamy S, Pan X, Mead D, Crane DD, Musser JM, Barry CE. 1998. Inhibition of a Mycobacterium tuberculosis β-ketoacyl ACP synthase by isoniazid. Science 280, 1607-1610. https://doi.org/10.1126/science.280.5369.1607.

Miggiano R, Rizzi M, Ferraris DM. 2020. Mycobacterium tuberculosis pathogenesis, infection prevention and treatment. Pathogens 9, 385. https://doi.org/10.3390/pathogens9050385.

Milano A, Pasca MR, Provvedi R, Lucarelli AP, Manina G, Ribeiro AL, Manganelli R, Riccardi G. 2009. Azole resistance in Mycobacterium tuberculosis is mediated by the MmpS5–MmpL5 efflux system. Tuberculosis 89, 84-90. https://doi.org/10.1016/j.tube.2008.08.003.

Mitchison DA. 1985. The action of antituberculosis drugs in short-course chemotherapy. Tubercle 66, 219-225. https://doi.org/10.1016/0041-3879(85)90040-6.

Mok S, Roycroft E, Flanagan PR, Montgomery L, Borroni E, Rogers TR, Fitzgibbon MM. 2021. Overcoming the challenges of pyrazinamide susceptibility testing in clinical Mycobacterium tuberculosis isolates. Antimicrobial Agents and Chemotherapy65, 10-128. https://doi.org/10.1128/AAC.02617-20.

Nahid P, Mase SR, Migliori GB, Sotgiu G, Bothamley GH, Brozek JL, Cattamanchi A, Cegielski JP, Chen L, Daley CL, Dalton TL. 2019. Treatment of drug-resistant tuberculosis. An official ATS/CDC/ERS/IDSA clinical practice guideline. American Journal of Respiratory and Critical Care Medicine 200, e93-142. https://doi.org/10.1164/rccm.201909-1874ST.

Nair J, Rouse DA, Bai GH, Morris SL. 1993. The rpsL gene and streptomycin resistance in single and multiple drug-resistant strains of Mycobacterium tuberculosis. Molecular Microbiology 10, 521-752. https://doi.org/10.1111/j.1365-2958.1993.tb00924.x.

Okamoto S, Tamaru A, Nakajima C, Nishimura K, Tanaka Y, Tokuyama S, Suzuki Y, Ochi K. 2007. Loss of a conserved 7-methylguanosine modification in 16S rRNA confers low-level streptomycin resistance in bacteria. Molecular Microbiology 63, 1096-1106. https://doi.org/10.1111/j.1365-2958.2006.05585.x.

Parish T, Roberts G, Laval F, Schaeffer M, Daffé M, Duncan K. 2007. Functional complementation of the essential gene fabG1 of Mycobacterium tuberculosis by Mycobacterium smegmatis fabG but not Escherichia coli fabG. Journal of Bacteriology 189, 3721-3728. https://doi.org/10.1128/JB.01740-06.

Plinke C, Rusch-Gerdes S, Niemann S. 2006. Significance of mutations in embB codon 306 for prediction of ethambutol resistance in clinical Mycobacterium tuberculosis isolates. Antimicrob Agents Chemother 50, 1900-1902. https://doi.org/10.1128/AAC.50.5.1900-1902.2006.

Prasad R, Gupta N, Banka A. 2018. Multidrug-resistant tuberculosis/rifampicin-resistant tuberculosis: Principles of management. Lung India 35, 78-81. https://doi.org/10.4103/lungindia.lungindia_98_17.

Reeves AZ, Campbell PJ, Sultana R, Malik S, Murray M, Plikaytis BB, Shinnick TM, Posey JE.2013. Aminoglycoside cross-resistance in Mycobacterium tuberculosis due to mutations in the 5′ untranslated region of whiB7. Antimicrobial Agents and Chemotherapy 57, 1857-1865. https://doi.org/10.1128/AAC.02191-12.

Rengarajan J, Sassetti CM, Naroditskaya V, Sloutsky A, Bloom BR, Rubin EJ. 2004. The folate pathway is a target for resistance to the drug para-aminosalicylic acid (PAS) in mycobacteria. Molecular Microbiology 53, 275-282. https://doi.org/10.1111/j.1365-2958.2004.04120.x.

Rodríguez-García Á, Mares-Alejandre RE,  Muñoz-Muñoz PL, Ruvalcaba-Ruiz S, González-Sánchez RA, Bernáldez-Sarabia J, Meléndez-López SG, Licea-Navarro AF, Ramos-Ibarra MA. 2021. Molecular analysis of Streptomycin resistance genes in clinical strains of Mycobacterium tuberculosis and biocomputational analysis of the Mt GidB L101F variant. Antibiotics 10, 807. https://doi.org/10.3390/antibiotics10070807.

Safi H, Lingaraju S, Amin A, Kim S, Jones M, Holmes M, McNeil M, Peterson SN, Chatterjee D, Fleischmann R, Alland D. 2013. Evolution of high-level ethambutol-resistant tuberculosis through interacting mutations in decaprenylphosphoryl-β-D-arabinose biosynthetic and utilization pathway genes. Nature Genetics 45, 1190. https://doi.org/10.1038/ng.2743.

Saier Jr MH, Yen MR, Noto K, Tamang DG, Elkan C.2008. The transporter classification database: recent advances. Nucleic Acids Research 37, D274-8. https://doi.org/10.1093/nar/gkn862

Scorpio A, Zhang Y. 1996. Mutations in pncA, a gene encoding pyrazinamidase/nicotinamidase, cause resistance to the antituberculous drug pyrazinamide in tubercle bacillus. Nature Medicine 2, 662. https://doi.org/10.1038/nm0696-662.

Shafipour M, Shirzad-Aski H, Mohammadzadeh A, Ghazvini K, Zamani S, Koohi PM, Ghaemi S, Ghaemi EA. 2022. Evaluation of mutations related to streptomycin resistance in Mycobacterium tuberculosis clinical isolates. Current Microbiology 79, 343. https://doi.org/10.1007/s00284-022-03043-9.

Shi D, Li L, Zhao Y, Jia Q, Li H, Coulter C, Jin Q, Zhu G. 2011. Characteristics of embB mutations in multidrug-resistant Mycobacterium tuberculosis isolates in Henan, China. Journal of Antimicrobial Chemotherapy 66, 2240-2247. https://doi.org/10.1093/jac/dkr284.

Sinha P, Srivastava GN, Tripathi R, Mishra MN, Anupurba S. 2020. 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 Microbiology 20,1-8. https://doi.org/10.1186/s12866-020-01967-5.

Stemkens R, Jager VD, Dawson R, Diacon AH, Narunsky K, Padayachee SD, Boeree MJ, van Beek SW, Colbers A, Coenen MJ, Svensson EM. 2023. Drug interaction potential of high-dose rifampicin in patients with pulmonary tuberculosis. Antimicrobial Agents and Chemotherapy 67, e00683-23. https://doi.org/10.1128/aac.00683-23.

Telenti A, Philipp WJ, Sreevatsan S, Bernasconi C, Stockbauer KE, Wieles B, Musser JM, Jacobs Jr WR. 1997. The emb operon, a gene cluster of Mycobacterium tuberculosis involved in resistance to ethambutol. Nature Medicine 3, 567-570. https://doi.org/10.1038/nm0597-567.

Telenti A. 1997. Genetics of drug resistance in tuberculosis. Clinics in Chest Medicine 18, 55-64. https://doi.org/10.1016/s0272-5231(05)70355-5.

Vilchèze C, Jacobs Jr WR. 2014. Resistance to isoniazid and ethionamide in Mycobacterium tuberculosis: genes, mutations, and causalities. Microbiology Spectrum 2, 431-453. https://doi.org/10.1128/microbiolspec.MGM2-0014-2013.

Waller NJ, Cheung CY, Cook GM, McNeil MB. 2023. The evolution of antibiotic resistance is associated with collateral drug phenotypes in Mycobacterium tuberculosis. Nature Communications 14, 1517. https://doi.org/10.1038/s41467-023-37184-7.

Wang J, Zhao W, Liu R, Huo F, Dong L, Xue Y,  Wang Y, Xue Z, Ma L, Pang Y. 2020. Rapid Detection of Ethambutol-Resistant Mycobacterium tuberculosis from Sputum by High-Resolution Melting Analysis in Beijing, China. Infection and Drug Resistance 20, 3707-3713. https://doi.org/10.2147/IDR.S270542.

Wang Z, Tang Z, Heidari H, Molaeipour L, Ghanavati R, Kazemian H, Koohsar F, Kouhsari E. 2023. Global status of phenotypic pyrazinamide resistance in Mycobacterium tuberculosis clinical isolates: an updated systematic review and meta-analysis. Journal of Chemotherapy 35, 583-595. https://doi.org/10.1080/1120009X.2023.2214473.

Wilson TM, Collins DM. 1996. ahpC, a gene involved in isoniazid resistance of the Mycobacterium tuberculosis complex. Molecular Microbiology 19, 1025-1034. https://doi.org/10.1046/j.1365-2958.1996.449980.x.

WHO, World Health Organization. Global tuberculosis report, 2022. Geneva, Switzerland: World Health Organization 2022. Available at:  https://www.who.int/publications/i/item/9789240061729 (Accessed January 20, 2024).

Xu G, Liu H, Jia X, Wang X, Xu P. 2021. Mechanisms and detection methods of Mycobacterium tuberculosis rifampicin resistance: the phenomenon of drug resistance is complex. Tuberculosis 128, 102083. https://doi.org/10.1016/j.tube.2021.102083.

Zaczek A, Brzostek A, Augustynowicz-Kopec E, Zwolska Z, Dziadek J. 2009. Genetic evaluation of relationship between mutations in rpoB and resistance of Mycobacterium tuberculosis to rifampin. BMC Microbiology 9, 1-8. https://doi.org/10.1186/1471-2180-9-10.

Zaw MT, Emran NA, Lin Z. 2018. Mutations inside rifampicin-resistance determining region of rpoB gene associated with rifampicin-resistance in Mycobacterium tuberculosis. Journal of Infectio and Public Health 11, 605-610. https://doi.org/10.1016/j.jiph.2018.04.005.

Zeng MC, Jia QJ, Tang LM. 2021. rpoB gene mutations in rifampin-resistant Mycobacterium tuberculosis isolates from rural areas of Zhejiang, China. Journal of International Medical Research 49, 0300060521997596. https://doi.org/10.1177/0300060521997596.

Zenteno-Cuevas R, Cuevas-Córdoba B, Parissi-Crivelli A. 2019. rpoB, katG and inhA mutations in multi-drug resistant strains of Mycobacterium tuberculosis clinical isolates from southeast Mexico. Enfermedades Infecciosas y Microbiología Clínica  37, 307-313. https://doi.org/10.1016/j.eimc.2018.09.002.

Zhang M, Yue J, Yang YP, Zhang HM, Lei JQ, Jin RL, Zhang XL, Wang HH. 2005. Detection of mutations associated with isoniazid resistance in Mycobacterium tuberculosis isolates from China. Journal of Clinical Microbiology 43, 5477-5482. https://doi.org/10.1128/JCM.43.11.5477-5482.2005.

Zhang S, Chen J, Shi W, Liu W, Zhang W, Zhang Y. 2013. Mutations in panD encoding aspartate decarboxylase are associated with pyrazinamide resistance in Mycobacterium tuberculosis. Emerging Microbes and Infections 2, e34. https://doi.org/10.1038/emi.2013.38.

Zhang X, Liu L, Zhang Y, Dai G, Huang H, Jin Q. 2015. Genetic determinants involved in p-aminosalicylic acid resistance in clinical isolates from tuberculosis patients in northern China from 2006 to 2012. Antimicrobial Agents and Chemotherapy 59, 1320-1324. https://doi.org/10.1128/AAC.03695-14.

Zhang Y, Heym B, Allen B, Young D, Cole S. 1992. The catalase-peroxidase gene and isoniazid resistance of Mycobacterium tuberculosis. Nature  358, 591-593. https://doi.org/10.1038/358591a0.

Zhao LL, Sun Q, Liu HC, Wu XC, Xiao TY, Zhao XQ, Li GL, Jiang Y, Zeng CY, Wan KL. 2015. Analysis of embCAB mutations associated with ethambutol resistance in multidrug-resistant Mycobacterium tuberculosis isolates from China. Antimicrobial Agents and Chemotherapy 59, 2045-2050. https://doi.org/10.1128/AAC.04933-14.

Zhu C, Liu Y, Hu L, Yang M, He ZG. 2018. Molecular mechanism of the synergistic activity of ethambutol and isoniazid against Mycobacterium tuberculosis. Journal of Biological Chemistry 293, 16741–16750. https://doi.org/10.1074/jbc.RA118.002693.