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Table 1 Antitubercular drug-resistance mechanismsa

From: Deciphering drug resistance in Mycobacterium tuberculosis using whole-genome sequencing: progress, promise, and challenges

WHO categoryDrug or drug classResistance genesRv numberGene functionMechanism of drug resistanceReference(s)
First-line agentsRifamycins (for example, rifampicin)rpoBRv0667RNA polymeraseTarget modification[6]
ponA1Rv0050Probable bifunctional penicillin-binding proteinUnknown[7]
IsoniazidkatGRv1908cCatalase-peroxidase enzymeDecreased drug activation[8]
inhARv1484NADH-dependent enoyl-acyl carrier proteinTarget amplification or modification[9, 10]
PyrazinamidebpncARv2043cPyrazinamidaseDecreased drug activation[11, 12]
panDRv3601cAspartate decarboxylaseUnknown[13]
rpsARRv1630Ribosomal protein S1Target modification[14]
EthambutolbembCAB operonRv3793-5ArabinosyltransferaseTarget modification[15, 16]
ubiARv3806cArabinogalactan synthesisGain-of-function[15]
Group ALevofloxacin
Moxifloxacin
gyrARv0006DNA gyrase ATarget modification[17, 18]
gyrBRv0005DNA gyrase BTarget modification[18]
BedaquilineatpERv1305ATP synthaseTarget modification[19]
pepQRv2535cPutative Xaa-Pro aminopeptidaseUnknown[20]
Rv0678Rv0678Transcriptional regulator of mmpL5Drug efflux[21, 22]
LinezolidRrlNA23S rRNATarget modification[23]
rplCRv070150S ribosomal protein L3Target modification[24]
Group BClofaziminepepQRv2535cPutative Xaa-Pro aminopeptidaseDrug efflux[20]
Rv0678Rv0678Transcriptional regulator of mmpL5Drug efflux[21]
Cycloserine
Terizidone
AldRv2780L-alanine dehydrogenaseSubstrate shunting[25]
alrRv3423cAlanine racemaseTarget modification[26, 27]
ddlRv2981cD-alanine-D-alanine ligaseTarget modification[27]
cycARv1704cBacterial D-serine/L-and D-alanine/glycine/D-cycloserine proton symporterMechanism not confirmed[28]
Group CDelamanid
Pretomanid
ddnRv3547Oxidative stressDecreased drug activation[29]
fgd1Rv0407Glucose-6-phosphate oxidationDecreased drug activation[29]
Imipenem/cilastatincrfARv2421c-Rv2422 intergenicUnknownDrug inactivation[30]
Amikacin, Capreomycin, KanamycincRrsNA16S rRNATarget modification[31]
StreptomycinrpsLRv068212S ribosomal proteinTarget modification[32,33,34,35]
rrsNA16S rRNATarget modification[36]
gidBRv3919c7-Methylguanosine methyltransferaseTarget modification[37]
Ethionamide ProthionamideethARv3854cMono-oxygenaseDecreased drug activation[38, 39]
ethRRv3855Transcriptional regulatory repressor protein (TetR)Decreased drug activation[39]
inhARv1484NADH-dependent enoyl-acyl carrier proteinTarget amplification or modification[10]
Para-aminosalicylic acid (PAS)folCRv2447cFolate pathwayDecreased drug activation[40]
dfrARv2763cDihydrofolate reductaseTarget amplification[40]
thyARv2764cThymidylate synthaseTarget modification[41, 42]
thyXRv2754cCatalyzes dTMP and tetrahydrofolateMitigating target inhibition[43]
ribDRv2671Enzyme in riboflavin biosynthesisMitigating target inhibition[40, 44]
Other medicinescKanamycinEisRv2416cAminoglycoside acetyltransferaseInactivating mutation[45]
CapreomycintlyARv1694rRNA methyltransferaseTarget modification[46]
  1. Abbreviations: MDR-TB multidrug-resistant tuberculosis, NA not applicable, RR-TB rifampicin-resistant tuberculosis, WHO World Health Organization
  2. aAntitubercular drugs are listed by the 2018 WHO grouping of medicines recommended for use in longer, individualized MDR-TB regimens [47]. For each drug or drug class, the specific genes in which drug-resistance mutations are commonly identified are listed with their gene name, gene number (Rv number), gene function, and the confirmed or putative mechanisms of resistance. bPyrazinamide and ethambutol are first-line TB drugs that also are categorized as Group C medicines for the treatment of longer MDR-TB regimens. cKanamycin and capreomycin are no longer recommended to be included in longer, individualized MDR/RR-TB regimens
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