Table 1.
WHO category | Drug or drug class | Resistance genes | Rv number | Gene function | Mechanism of drug resistance | Reference(s) |
---|---|---|---|---|---|---|
First-line agents | Rifamycins (for example, rifampicin) | rpoB | Rv0667 | RNA polymerase | Target modification | [6] |
ponA1 | Rv0050 | Probable bifunctional penicillin-binding protein | Unknown | [7] | ||
Isoniazid | katG | Rv1908c | Catalase-peroxidase enzyme | Decreased drug activation | [8] | |
inhA | Rv1484 | NADH-dependent enoyl-acyl carrier protein | Target amplification or modification | [9, 10] | ||
Pyrazinamideb | pncA | Rv2043c | Pyrazinamidase | Decreased drug activation | [11, 12] | |
panD | Rv3601c | Aspartate decarboxylase | Unknown | [13] | ||
rpsA | RRv1630 | Ribosomal protein S1 | Target modification | [14] | ||
Ethambutolb | embCAB operon | Rv3793-5 | Arabinosyltransferase | Target modification | [15, 16] | |
ubiA | Rv3806c | Arabinogalactan synthesis | Gain-of-function | [15] | ||
Group A |
Levofloxacin Moxifloxacin |
gyrA | Rv0006 | DNA gyrase A | Target modification | [17, 18] |
gyrB | Rv0005 | DNA gyrase B | Target modification | [18] | ||
Bedaquiline | atpE | Rv1305 | ATP synthase | Target modification | [19] | |
pepQ | Rv2535c | Putative Xaa-Pro aminopeptidase | Unknown | [20] | ||
Rv0678 | Rv0678 | Transcriptional regulator of mmpL5 | Drug efflux | [21, 22] | ||
Linezolid | Rrl | NA | 23S rRNA | Target modification | [23] | |
rplC | Rv0701 | 50S ribosomal protein L3 | Target modification | [24] | ||
Group B | Clofazimine | pepQ | Rv2535c | Putative Xaa-Pro aminopeptidase | Drug efflux | [20] |
Rv0678 | Rv0678 | Transcriptional regulator of mmpL5 | Drug efflux | [21] | ||
Cycloserine Terizidone |
Ald | Rv2780 | L-alanine dehydrogenase | Substrate shunting | [25] | |
alr | Rv3423c | Alanine racemase | Target modification | [26, 27] | ||
ddl | Rv2981c | D-alanine-D-alanine ligase | Target modification | [27] | ||
cycA | Rv1704c | Bacterial D-serine/L-and D-alanine/glycine/D-cycloserine proton symporter | Mechanism not confirmed | [28] | ||
Group C |
Delamanid Pretomanid |
ddn | Rv3547 | Oxidative stress | Decreased drug activation | [29] |
fgd1 | Rv0407 | Glucose-6-phosphate oxidation | Decreased drug activation | [29] | ||
Imipenem/cilastatin | crfA | Rv2421c-Rv2422 intergenic | Unknown | Drug inactivation | [30] | |
Amikacin, Capreomycin, Kanamycinc | Rrs | NA | 16S rRNA | Target modification | [31] | |
Streptomycin | rpsL | Rv0682 | 12S ribosomal protein | Target modification | [32–35] | |
rrs | NA | 16S rRNA | Target modification | [36] | ||
gidB | Rv3919c | 7-Methylguanosine methyltransferase | Target modification | [37] | ||
Ethionamide Prothionamide | ethA | Rv3854c | Mono-oxygenase | Decreased drug activation | [38, 39] | |
ethR | Rv3855 | Transcriptional regulatory repressor protein (TetR) | Decreased drug activation | [39] | ||
inhA | Rv1484 | NADH-dependent enoyl-acyl carrier protein | Target amplification or modification | [10] | ||
Para-aminosalicylic acid (PAS) | folC | Rv2447c | Folate pathway | Decreased drug activation | [40] | |
dfrA | Rv2763c | Dihydrofolate reductase | Target amplification | [40] | ||
thyA | Rv2764c | Thymidylate synthase | Target modification | [41, 42] | ||
thyX | Rv2754c | Catalyzes dTMP and tetrahydrofolate | Mitigating target inhibition | [43] | ||
ribD | Rv2671 | Enzyme in riboflavin biosynthesis | Mitigating target inhibition | [40, 44] | ||
Other medicinesc | Kanamycin | Eis | Rv2416c | Aminoglycoside acetyltransferase | Inactivating mutation | [45] |
Capreomycin | tlyA | Rv1694 | rRNA methyltransferase | Target modification | [46] |
Abbreviations: MDR-TB multidrug-resistant tuberculosis, NA not applicable, RR-TB rifampicin-resistant tuberculosis, WHO World Health Organization
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