Immunology of Drug-Resistant Tuberculosis (DR-TB):A Literature Review
DOI:
https://doi.org/10.36497/jri.v45i4.958Keywords:
drug-resistant, immunological mechanism, tuberculosisAbstract
Drug-resistant tuberculosis (DR-TB) poses significant challenges to control efforts due to its complex pathogenesis and limited treatment options. DR-TB arises through primary infection with resistant strains or secondary resistance during the course of treatment. Secondary resistance is divided into intrinsic and acquired. In intrinsic resistance, infection is caused by TB germs that have evolved, causing resistance through several mechanisms, namely reducing cell membrane permeability, drug reflux, degradation and target modification, while acquired resistance is caused by chromosomal mutations in target genes during the treatment process. Resistance is driven by chromosomal mutations in key genes such as rpoB, katG, inhA, pncA, emb, gyrA/gyrB, rrs and others, leading to reduced drug susceptibility. This review summarizes immunological mechanisms relevant to resistance and current treatment approaches.
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References
1. World Health Organization. Global tuberculosis report 2023. Geneva: World Health Organization; 2023.
2. Kementerian Kesehatan Republik Indonesia. Laporan program penanggulangan tuberkulosis tahun 2022. Jakarta: Kementerian Kesehatan Republik Indonesia; 2023. 1–147 p.
3. Direktorat Jenderal Pencegahan dan Pengendalian Penyakit (P2P) Kementerian Kesehatan RI. Petunjuk teknis penatalaksanaan tuberkulosis resistan obat di Indonesia. Indonesia; 2024. p. 1–4.
4. Dheda K, Gumbo T, Maartens G, Dooley KE, McNerney R, Murray M, et al. The epidemiology, pathogenesis, transmission, diagnosis, and management of multidrug-resistant, extensively drug-resistant, and incurable tuberculosis. Lancet Respir Med. 2017;5(4):291–360.
5. World Health Organization. WHO consolidated guidelines on tuberculosis. Module 4: treatment - drug-resistant tuberculosis treatment, 2022 update. Geneva; 2022.
6. Direktorat Jenderal Pencegahan dan Pengendalian Penyakit (P2P) Kementerian Kesehatan RI. Petunjuk teknis penatalaksanaan tuberkulosis resistan obat di Indonesia. Indonesia; 2023.
7. Tiberi S, Utjesanovic N, Galvin J, Centis R, D’Ambrosio L, van den Boom M, et al. Drug resistant TB – latest developments in epidemiology, diagnostics and management. International Journal of Infectious Diseases. 2022;124(Suppl 1):S20–5.
8. Direktorat Jenderal Pencegahan dan Pengendalian Penyakit (P2P) Kementerian Kesehatan RI. Petunjuk teknis penatalaksanaan tuberkulosis resistan obat di Indonesia. Indonesia; 2020.
9. Jang JG, Chung JH. Diagnosis and treatment of multidrug-resistant tuberculosis. Yeungnam Univ J Med. 2020;37(4):277–85.
10. Goossens SN, Sampson SL, Van Rie A. Mechanisms of drug-induced tolerance in mycobacterium tuberculosis. Clin Microbiol Rev. 2021;34(1):e00141-20.
11. Centers for Disease Control and Prevention. Clinical overview of drug-resistant tuberculosis disease [Internet]. 2025 [cited 2025 Oct 2]. Available from: https://www.cdc.gov/tb/hcp/clinical-overview/drug-resistant-tuberculosis-disease.html?
12. Vadakunnel MJ, Nehru VJ, Brammacharry U, Ramachandra V, Palavesam S, Muthukumar A, et al. Impact of rpoB gene mutations and rifampicin-resistance levels on treatment outcomes in rifampicin-resistant tuberculosis. BMC Infect Dis. 2025;25(1):284.
13. Nono VN, Nantia EA, Mutshembele A, Teagho SN, Simo YWK, Takong BS, et al. Prevalence of katG and inhA mutations associated with isoniazid resistance in mycobacterium tuberculosis clinical isolates in Cameroon. BMC Microbiology 2025 25:1. 2025;25:127.
14. World Health Organization. WHO consolidated guidelines on tuberculosis: module 4: treatment and care. Geneva; 2025.
15. Rossini N de O, Dias MVB. Mutations and insights into the molecular mechanisms of resistance of Mycobacterium tuberculosis to first-line drugs. Genet Mol Biol. 2023;46(1 Suppl 2):e20220261.
16. Kebede AH, Mamo H. Multidrug-resistant tuberculosis treatment outcomes and associated factors at Yirgalem General Hospital, Sidama Region, South Ethiopia: A retrospective cohort study. BMC Pulm Med. 2024;24(1):527.
17. Sharma RK, Kumari U, Kumari N, Kumar R. Characterization of genetic mutations in multi-drug-resistant isolates of Mycobacterium tuberculosis bacilli conferring resistance to a second-line anti-tuberculosis drug. Cureus. 2023;15(6):e40442.
18. Putra ON, Purnamasari T. Treatment outcomes of fluoroquinolone-resistant multidrug-resistant tuberculosis: An implication for delamanid. Tuberc Respir Dis (Seoul). 2024;87(2):206–8.
19. Pang Y, Zong Z, Huo F, Jing W, Ma Y, Dong L, et al. In vitro drug susceptibility of bedaquiline, delamanid, linezolid, clofazimine, moxifloxacin, and gatifloxacin against extensively drug-resistant tuberculosis in Beijing, China. Antimicrob Agents Chemother. 2017;61(10):e00900-17.
20. Sikandar M, Xing L. Advances in the mechanisms of drug resistance of Mycobacterium tuberculosis. Microb Pathog. 2025 Sep;206:107861.
21. Bei C, Fu M, Zhang Y, Xie H, Yin K, Liu Y, et al. Mortality and associated factors of patients with extensive drug-resistant tuberculosis: An emerging public health crisis in China. BMC Infect Dis. 2018;18.
22. Alsayed SSR, Gunosewoyo H. Tuberculosis: Pathogenesis, current treatment regimens and new drug targets. Int J Mol Sci. 2023;24(6):5202.
23. Maison DP. Tuberculosis pathophysiology and anti-VEGF intervention. J Clin Tuberc Other Mycobact Dis. 2022;27:100300.
24. Luies L, Preez I du. The echo of pulmonary tuberculosis: Mechanisms of clinical symptoms and other disease-induced systemic complications. Clin Microbiol Rev. 2020;33(4):e00036-20.
25. Harriff MJ, Cansler ME, Toren KG, Canfield ET, Kwak S, Gold MC, et al. Human lung epithelial cells contain Mycobacterium tuberculosis in a late endosomal vacuole and are efficiently recognized by CD8+ T Cells. PLoS One. 2014;9(5):e97515.
26. Stamm CE, Collins AC, Shiloh MU. Sensing of Mycobacterium tuberculosis and consequences to both host and bacillus. Immunol Rev. 2015;264(1):204–19.
27. Mi J, Wu X, Liang J. The advances in adjuvant therapy for tuberculosis with immunoregulatory compounds. Front Microbiol. 2024;15:1380848.
28. Queval CJ, Song OR, Carralot JP, Saliou JM, Bongiovanni A, Deloison G, et al. Mycobacterium tuberculosis controls phagosomal acidification by targeting CISH-mediated signaling. Cell Rep. 2017;20(13):3188–98.
29. Guo S, Xue R, Li Y, Wang SM, Ren L, Xu JJ. The CFP10/ESAT6 complex of Mycobacterium tuberculosis may function as a regulator of macrophage cell death at different stages of tuberculosis infection. Med Hypotheses. 2012;78(3):389–92.
30. Kroon EE, Coussens AK, Kinnear C, Orlova M, Möller M, Seeger A, et al. Neutrophils: Innate effectors of TB resistance? Front Immunol. 2018;9:2637.
31. Lowe DM, Demaret J, Bangani N, Nakiwala JK, Goliath R, Wilkinson KA, et al. Differential effect of viable versus necrotic neutrophils on Mycobacterium tuberculosis growth and cytokine induction in whole blood. Front Immunol. 2018;9:903.
32. Philips JA, Ernst JD. Tuberculosis pathogenesis and immunity. Annu Rev Pathol. 2012;7:353–84.
33. Mihret A. The role of dendritic cells in Mycobacterium tuberculosis infection. Virulence. 2012;3(7):654–9.
34. de Martino M, Lodi L, Galli L, Chiappini E. Immune response to mycobacterium tuberculosis: A narrative review. Front Pediatr. 2019;7:350.
35. Lim JJ, Grinstein S, Roth Z. Diversity and versatility of phagocytosis: Roles in innate immunity, tissue remodeling, and homeostasis. Front Cell Infect Microbiol. 2017;7.
36. Kumar V, Abbas AK, Aster JC. Robbins & Cotran pathologic basis of disease. 10th ed. Kumar V, Abbas AK, Aster JC, editors. Elsevier; 2020. 713–65 p.
37. Domingo-Gonzalez R, Prince O, Cooper A, Khader SA. Cytokines and chemokines in Mycobacterium tuberculosis infection. Microbiol Spectr. 2016;4(5):TBTB2-0018–2016.
38. Nguyen L. Antibiotic resistance mechanisms in M. tuberculosis: An update. Arch Toxicol. 2016;90(7):1585–604.
39. Jacobo-Delgado YM, Rodríguez-Carlos A, Serrano CJ, Rivas-Santiago B. Mycobacterium tuberculosis cell-wall and antimicrobial peptides: A mission impossible? Front Immunol. 2023;14:1194923.
40. Gauba A, Rahman KM. Evaluation of antibiotic resistance mechanisms in gram-negative bacteria. Antibiotics. 2023;12(11):1590.
41. Nasiri MJ, Haeili M, Ghazi M, Goudarzi H, Pormohammad A, Fooladi AAI, et al. New insights in to the intrinsic and acquired drug resistance mechanisms in mycobacteria. Front Microbiol. 2017;8:681.
42. Singh R, Dwivedi SP, Gaharwar US, Meena R, Rajamani P, Prasad T. Recent updates on drug resistance in Mycobacterium tuberculosis. J Appl Microbiol. 2020;128(6):1547–67.
43. Smith T, Wolff KA, Nguyen L. Molecular biology of drug resistance in Mycobacterium tuberculosis. Curr Top Microbiol Immunol. 2013;374:53–80.
44. Nasiruddin M, Neyaz MdK, Das S. Nanotechnology-based approach in tuberculosis treatment. Tuberc Res Treat. 2017;2017:4920209.
45. Tao J, Han J, Wu H, Hu X, Deng J, Fleming J, et al. Mycobacterium fluoroquinolone resistance protein B, a novel small GTPase, is involved in the regulation of DNA gyrase and drug resistance. Nucleic Acids Res. 2013;41(4):2370–81.
46. Ministry of Health Ethiopia. Tuberculosis, leprosy and other lung diseases control desk clinical and programmatic management of drug resistant TB in Ethiopia. Ethiopia; 2023.
47. Khawbung JL, Nath D, Chakraborty S. Drug resistant tuberculosis: A review. Comp Immunol Microbiol Infect Dis. 2021;74:101574.
48. Piccaro G, Pietraforte D, Giannoni F, Mustazzolu A, Fattorini L. Rifampin induces hydroxyl radical formation in Mycobacterium tuberculosis. Antimicrob Agents Chemother. 2014;58(12):7527–33.
49. Islam MM, Hameed HMA, Mugweru J, Chhotaray C, Wang C, Tan Y, et al. Drug resistance mechanisms and novel drug targets for tuberculosis therapy. Journal of Genetics and Genomics. 2017;44(1):21–37.
50. Miotto P, Zhang Y, Cirillo DM, Yam WC. Drug resistance mechanisms and drug susceptibility testing for tuberculosis. Respirology. 2018;23(12):1098–113.
51. Klopper M, Warren RM, Hayes C, van Pittius NCG, Streicher EM, Müller B, et al. Emergence and spread of extensively and totally drug-resistant tuberculosis, South Africa. Emerg Infect Dis. 2013;19(3):449–55.
52. He L, Wang X, Cui P, Jin J, Chen J, Zhang W, et al. UbiA (Rv3806c) encoding DPPR synthase involved in cell wall synthesis is associated with ethambutol resistance in Mycobacterium tuberculosis. Tuberculosis. 2015;95(2):149–54.
53. Lu J, Liu M, Wang Y, Pang Y, Zhao Z. Mechanisms of fluoroquinolone monoresistance in Mycobacterium tuberculosis. FEMS Microbiol Lett. 2014;353(1):40–8.
54. Garneau-Tsodikova S, Labby KJ. Mechanisms of resistance to aminoglycoside antibiotics: Overview and perspectives. Medchemcomm. 2016;7(1):11–27.
55. Kambli P, Ajbani K, Nikam C, Sadani M, Shetty A, Udwadia Z, et al. Correlating rrs and eis promoter mutations in clinical isolates of Mycobacterium tuberculosis with phenotypic susceptibility levels to the second-line injectables. Int J Mycobacteriol. 2016;5(1):1–6.
56. Laughlin ZT, Conn GL. Tuberactinomycin antibiotics: Biosynthesis, anti-mycobacterial action, and mechanisms of resistance. Front Microbiol. 2022;13:961921.
57. Laurenzo D, Mousa SA. Mechanisms of drug resistance in Mycobacterium tuberculosis and current status of rapid molecular diagnostic testing. Acta Trop. 2011;119(1):5–10.
58. Zhao F, Wang X De, Erber LN, Luo M, Guo AZ, Yang SS, et al. Binding pocket alterations in dihydrofolate synthase confer resistance to para-aminosalicylic acid in clinical isolates of Mycobacterium tuberculosis. Antimicrob Agents Chemother. 2014;58(3):1479–87.
59. Desjardins CA, Cohen KA, Munsamy V, Abeel T, Maharaj K, Walker BJ, et al. Genomic and functional analyses of Mycobacterium tuberculosis strains implicate ald in D-cycloserine resistance. Nat Genet. 2016;48(5):544–51.
60. Shi W, Zhang S, Feng J, Cui P, Zhang W, Zhang Y. Clofazimine targets essential nucleoid associated protein, mycobacterial integration host factor (mIHF), in Mycobacterium tuberculosis. bioRxiv. 2017;12.
61. Xu J, Wang B, Hu M, Huo F, Guo S, Jing W, et al. Primary clofazimine and bedaquiline resistance among isolates from patients with multidrug-resistant tuberculosis. Antimicrob Agents Chemother. 2017;61(6):e00239-17.
62. Bobba S, Khader SA. Rifampicin drug resistance and host immunity in tuberculosis: More than meets the eye. Trends Immunol. 2023;44(9):712–23.
63. Esmail H, Riou C, Bruyn E Du, Lai RPJ, Harley YXR, Meintjes G, et al. The immune response to Mycobacterium tuberculosis in HIV-1-coinfected persons. Annu Rev Immunol. 2018;36:603–38.
64. Aguilar Diaz JM, Abulfathi AA, Te Brake LHM, Van Ingen J, Kuipers S, Magis-Escurra C, et al. New and repurposed drugs for the treatment of active tuberculosis: An update for clinicians. Respiration. 2023;102(2):83–100.
65. Johnson TM, Rivera CG, Lee G, Zeuli JD. Pharmacology of emerging drugs for the treatment of multi-drug resistant tuberculosis. J Clin Tuberc Other Mycobact Dis. 2024 Dec 1;37:100470.
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