Molecular mechanisms of underlying genetic factors and associated mutations for drug resistance in Mycobacterium tuberculosis

Figures & data

Figure 1. Successful anti-TB drugs from natural sources.

Figure 2. A schematic representation of the drug-resistant mechanism of mycobacterium tuberculosis.

Figure 3. A schematic representation of genetic mutations associated with the drug-resistant mechanism of rifampicin targeting rpoB.

Table 1. Genetic factors involved in first-line anti-TB drug resistance in Mycobacterium tuberculosis.

Drug (year)	Chemical class (activity type)	Inhibition target (associated action)	MIC (mg/L)	Genetic factor	Associated function	Drug resistance	Reference
Isoniazid (1952)	Isonicotinic acid (bactericidal)	Enoyl-(acyl-carrier-protein) reductase including, catalase peroxidase, NADH-dependent enoyl ACP, 3-Oxoacy ACP, β-Ketoacyl ACP) (inhibition of cell wall synthesis)	0.02-0.2	katG	Intracellular survival	Modification overexpression of drug target due to mutations and altered efflux pump activity and pro-drug conversion	[28,29]
				inhA	Mycolic acid biosynthesis
				kasA	Fatty acid biosynthesis
				AhpC	Defence from oxidative stress
				niA	Associated with efflux pump
				FadE24	Degradation lipid and fatty acid
				ndh	Electron transference from NADH to the respiratory chain
				FabG1	Fatty acid biosynthesis pathway
Rifampicin (1963)	Rifamycin (bactericidal)	RNA polymerase, β-subunit (inhibition of RNA synthesis)	0.05-1.0	rpoB rpoA rpoC	Catalyze the transcription for DNA into RNA synthesis	Modification in drug target due to mutations	[30,31]
Ethambutol (1961)	Ethylenediamine (bacteriostatic)	Arabinosyl transferase (inhibition of arabinogalactan synthesis)	1–5	emb A, B and C	Associated with biosynthesis of the mycobacterial cell wall	Change and overexpression of drug target; and altered efflux pump activity	[29,32]
				embR	embCAB operon synthesis regulator
				rmLD	dTDP-L-rhamnose biosynthesis
				iniA	Associated with efflux pump
Pyrazinamide (1952)	Pyrazine (bacteriostatic/bactericidal)	Pyrazinamidase; ribosomal protein 1 30S ribosomal subunit, cytoplasm	16–100	pncA	To converts amides into acid	Abolition of pro-drug conversion mechanism	[33,34]
				rpsA	Translate mRNA with a shine-dalgarno purine-rich sequence
				panD	Pantothenate biosynthesis
				clpC1	Protein degradation, hydrolyses proteins in the presence of ATP
				gpsI	Involved in mRNA degradation
Streptomycin (1944)*	Aminoglycoside (bacteriostatic)	30S, 16S ribosomal protein and 7-methyl guanosine methyl-transferase (inhibition of arabinoga-lactan and protein synthesis)	2–8	rpsL	Translation initiation step	Variation in drug target binding site due to mutations	[35,36]
				rrs	Synthesis of stable RNAs
				gidB	Probable glucose-inhibited division protein B

*, injectable.

Table 2. Genetic factors involved in second-line anti-TB drug resistance in Mycobacterium tuberculosis.

Drug (year)	Chemical class (activity type)	Inhibition target (associated action)	MIC (mg/L)	Genetic factor	Associated function	Drug resistance	Reference
Moxifloxacin (1996) Gatifloxacin (1999)	Quinolones/8-methoxyfluroquinolone (bactericidal)	DNA gyrase and DNA topoisomerase (Inhibits DNA synthesis)	0.5–2.5	gyrA, gyrB	Negatively supercoils closed circular double-stranded DNA	Alteration of drug target due to mutation	[29,37]
Kanamycin* (1957) Amikacin* (1972)	Amino-glycosides (bactericidal)	Inhibition of RNA-dependent synthesis by binding to 30S subunit (inhibition of protein synthesis)	2–8	rrs	Synthesis of stable RNAs	Mutations on 16S rRNA and overexpression machines	[36,38]
				eis	Acetylation, intracellular survival
				whiB7	Associated with transcription
				tlyA	Methylates 16S and 23S rRNA
Capreomycin* (1963)	Cyclic polypeptide (bactericidal)	Inhibition of 50S subunit (inhibition of protein synthesis)	2–4	rrs	Synthesis of stable RNAs	Mutation alteration drug target	[39,40]
				tlyA	Methylates 16S and 23S rRNA
				eis	Acetylation, intracellular survival
Ethionamide (1956)	Isoconitic acid derivative (bacteriostatic)	Inhibition of mycolic acid synthesis by binding to the ACP reductase InhA (disrupts cell wall biosynthesis)	2.5–25	ethA	Activates the pro-drug ethionamide	alteration and over-expression drug target due mutation	[40,42]
				ethR	Regulates transcriptional repressor protein EthR
				KasA	Involved in fatty acid biosynthesis
				inhA	Mycolic acid biosynthesis
				inhA pro.	Regulation of expression of inhA
Para-amino salicylic acid (1946)	Para-amino salicylic acid (bacteriostatic)	Dihydropteroate synthase (inhibits folate and thymine nucleotide metabolism biosynthesis)	1–8	thyA	Deoxyribo-nucleotide biosynthesis	Removal of pro-drug conversion procedure	[36,42]
				folC	Regulate folates to polyglutamate conversion
				dfrA	De novo glycine and purine synthesis
				ribD	Involved in riboflavin biosynthesis
Cycloserine (1955)	Serine derivative (bacteriostatic)	Inhibition of peptide-glycan synthesis by blocking d-alanine racemase enzyme (inhibition of cell wall synthesis)	25–30	alr	Associated with d-alanine required for cell wall biosynthesis	Overexpression of resistance gene	[43,44]
				ddl	Involved in cell wall formation
				Ald	Associated with cell wall synthesis
				cycA	Transport across the cytoplasmic membrane

*, injectable.

Table 3. Genetic factors involved in third-line anti-TB drug resistance in Mycobacterium tuberculosis.

Drug (year)	Chemical class (activity type)	Inhibition target (associated action)	MIC (mg/mL)	Genetic factor	Associated function	Drug resistance	Reference
Clofazimine (1954)	Iminophenazine derivative (bacteriostatic)	Produces reactive oxygen, inhibits energy production, potassium transporter (inhibition of mycobacterial growth targeting mycobacterial DNA)	0.1–1.2	rv0678	Transcription repressor for efflux pump MmpL5	Upregulation of MmpL5, efflux pump due to mutation	[45,46]
				rv1979c	Role in the transportation of amino acid
				rv2535c	Associated/encodes a putative peptidase PepQ.
				ndh	Associated with oxidation and reduction reaction
				pepQ	Possibly hydrolyse peptides
Bedaquiline (2012)	Quinoline (bactericidal/ bacteriostatic)	Inhibits the adenosine 5'-triphosphate synthase (inhibition of ATP synthase)	0.06–1	rv0678	Transcription of efflux pump MmpL5	Mutations on binding site and co-infection	[47–48]
				atpE	Encodes the c part of the F0 subunit of the ATP synthase
				pepQ	Possibly hydrolyses peptides
Delamanid (2014) Pretomanid (2020)	Nitroimidazole (bactericidal)	Obstructs the synthesis of mycolic acid	0.006–0.24/0.015–0.25	fgd1	Catalyzes oxidation of glucose-6-phosphate to 6-phosphogluconolactone	Mutations on reductive activating gene	[49–51]
				fbiC	Participates in a portion of the F420 biosynthetic pathway
				fbiA	Required for coenzyme F420 production from FO
				fbiB	Required for coenzyme F420 production from FO
				ddn	Converts bicyclic nitroimidazole drug candidate pa-824–3 metabolites
Linezolid (2000)	Oxazolidinone (bactericidal)	50S, 23S ribosomal subunit (inhibition of protein synthesis)	0.25–0.5	rplC	Formation of ribosomal peptidyl-transferase	Mutation in 50S ribosomal L3 protein	[52,53]
				rrl	Formation of stable RNAs

Figure 4. Newly identified anti-TB drug development targets and pipeline drugs.

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