Molecular Mechanism of Multi-drug Resistance in Mycobacterium tuberculosis

Anti-TB drugs and molecular mechanism of multi-drug resistance with regards to First Line- Line Probe Assay (FL-LPA) and Second Line- LPA (SL-LPA) is described here.

Rifampicin (RIF)

• It has a bactericidal effect on metabolically active M. tuberculosis and late sterilizing action on semi-dormant organisms undergoing short bursts of metabolic activity
• The mechanism of action of Rifampicin is the inhibition of RNA transcription in the mycobacterial cell by targeting DNA dependent RNA polymerase gene rpo B
• Resistance is due to mutations leading to a change in the structure of the beta subunit of Mycobacterium tuberculosis RNA polymerase

Isoniazid (INH)

• It has a potent early bactericidal action
• It is a pro-drug that requires activation by the mycobacterial enzyme, Catalase peroxidase gene katg
• INH resistant clinical isolates frequently lose their catalase peroxidase activity

INH may act on several targets within the mycobacterial cell, significant evidence supports the concept that it blocks the synthesis of cell wall mycolic acids. The major components of the envelope of M. tuberculosis.

Genes targeted in mycolic acid synthesis include:

• nadh-dependent enoyl acp synthase (encoded by inha)
• malonyl-coa acyl carrier protein (acp) transacylase (fabd)
• acetyl-coa carboxylase (accd6)

Other isoniazid target genes include peroxiredoxin alkyl hydroperoxide reductase subunit c (ahpc), ahpc-oxyrintergenic regulatory region; several efflux proteins encoded by iniabc and efpa

• Resistance is due to
  • Mutations in katg, fabg1, oxyr- ahpc intergenic region, accd6 and efflux proteins
  • Promoter region of inha, which leads to overexpression of isoniazid's target inha, requiring higher doses of the drug to achieve complete inhibition

Ethionamide (Eto)

• It has a bacteriostatic or bactericidal action, depending on the drug concentration in host
• It is a pro-drug, converted to active form by the bacterial monooxygenase EthA
• It targets mycolic acid synthesis
• Resistance is due to mutations in the inhA promoter

Pyrazinamide (Z)

• It has a bactericidal action; kills nonreplicating persistent Mycobacterium tuberculosis in macrophages
• It inhibits the synthesis of fatty acids; this disrupts the Mycobacterium tuberculosis cell membrane
• It is a pro-drug which must be activated by pyrazinamidase encoded by pncA, rpsA, and panD genes
• Resistance is due to mutation in pncA, rpsA, and panD; active drug effflux

Fluoroquinolones (Ofloxacin, Ofx; Levofloxacin, Lfx; Moxifloxacin, Mfx; Gatifloxacin, Gfx)

• Have a bactericidal action
• Inhibits gyrases encoded by gyrA and gyrB genes
• Prevent bacterial DNA synthesis
• High-level resistance requires multiple mutations in gyrA, or concurrent mutations in both gyrA and gyrB

Aminoglycosides (Kanamycin, Km; Amikacin, Am) /Polypeptides (Capreomycin, Cm)

• Have a bactericidal action
• Acts on ribosome rrs gene
• Prevents bacterial protein synthesis
• Resistance is due to mutation in rrs
• Low-level resistance to Kanamycin is associated with the promoter region of eis (enhanced intracellular survival protein) gene

Resources

• Guidelines for PMDT in India, 2021.​
• Tackling the Drug Resistance Crisis.

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