Table 3.
Anti-mycobacterial drugs and mechanisms of drug resistance.
| Agent | Mode of action | Target | Proven utility for (MIC μg/ml) | Gene | Gene function | Most prevalent mutation | References |
|---|---|---|---|---|---|---|---|
| Isoniazid | Inhibition of mycolic acid synthesis | Mycolic acids | M. tuberculosis (0.02–0.1 in 7H10) | katG | Catalase-peroxidase | Ser-315-Thr | OFFICIAL, 1990; National Committee for Clinical Laboratory Standards (NCCLS), 2000; Somoskovi et al., 2001; Ramaswamy et al., 2003; Zhang et al., 2005; Guo et al., 2006 |
| inhA | Enoyl ACP reductase | C-15-T SNP | |||||
| Ndh | NADH dehydrogenase II | Arg-13-Cys, Val-18-Ala | |||||
| ahpC | Alkyl hidroperoxidase | C-39-T, G-9-A, SNPs | |||||
| kasA | b-ketoacyl-ACP synthase | Gly-269-Ser | |||||
| Rifampicin | Inhibition of RNA polymerase | RNA polymerase | M. tuberculosis (1 in 7H10) M. kansasii (2) M. marinum (1) | rpoB | B-subunit of RNA polymerase | Ser-450-Leu | OFFICIAL, 1990; Heep et al., 2001; Somoskovi et al., 2001; Philley and Griffith, 2015 |
| Pyrazinamide | Inhibition of energy production and trans-translation | Fatty acid synthase-I, ribosomal protein S1 | M. tuberculosis (16–50 in LJ) | pncA | Pyrazinamidase | Asp-12-Ala/Asn,Leu-85-Pro | Somoskovi et al., 2001; Shi et al., 2011; Feuerriegel et al., 2013; Zhang et al., 2013, 2014 |
| rpsA | S1 ribosomal protein | Deletion Ala438, Thr-5-Ala | |||||
| panD | Aspartate decarboxylase | Ala-128-Ser, Val-138-Aal | |||||
| Ethambutol | Inhibition of arabinogalactan synthesis | Arabinosyl transferases | M. tuberculosis (5 in 7H10) M. kansasii (5) M. marinum (5) | embCAB | Arabinosyl transferases | Met-306-Val/Ile/Leu | OFFICIAL, 1990; Brown-Elliott et al., 2012; Palomino and Martin, 2014; Philley and Griffith, 2015 |
| Streptomycin | Inhibition of protein synthesis | 30S ribosomal subunit | M. tuberculosis (2–10 in 7H10) | rpsL rrs gidB | S12 ribosomal protein 16S rRNA 16S rRNAmethyltransferase | Lis-43-Arg A-1401-G SNP Leu-16-Arg | OFFICIAL, 1990; Finken et al., 1993; Da Silva and Palomino, 2011; Verma et al., 2014; Philley and Griffith, 2015 |
| Amikacin/Kanamycin | Inhibition of protein synthesis | 30S ribosomal subunit | M. tuberculosis (5 in 7H10) | Rrs | 16S rRNA | A-1401-G SNP | OFFICIAL, 1990; Zaunbrecher et al., 2009; Da Silva and Palomino, 2011; Georghiou et al., 2012; Kasperbauer and De Groote, 2015; Philley and Griffith, 2015 |
| M. kansasii (32) | Eis | Aminoglycoside acetyltransferase | G-37-T, G-10-A, G-14-T SNPs | ||||
| M. marinum (32) | |||||||
| RGM (64) | |||||||
| Capreomycin/viomycin | Inhibition of protein synthesis | 30S and 50S ribosome subunits | M. tuberculosis (10 in 7H10) | rrs | 16S rRNA | A-1401-G SNP | Johansen et al., 2006; Da Silva and Palomino, 2011; Georghiou et al., 2012 |
| tylA | rRNA methyltransferase | G-223-T SNP | |||||
| Eis | Aminoglycoside acetyltransferase | G-37-T, C-12-T SNPs | |||||
| Ethionamide | Inhibition of mycolic acid synthesis | Mycolic acids | M. tuberculosis (5 in 7H10) | ethA | Monooxygenase | Leu-397-Arg, Leu-328-Met | Morlock et al., 2003; Boonaiam et al., 2010; Brossier et al., 2011 |
| inhA | Enoyl-ACP reductase | Ile-21-Thr/Val, Ser-94-Ala | |||||
| Ndh | NADH dehydrogenase | Arg-13-Cys, Val-18-Ala | |||||
| mshA | Glycosyl transferase | Val-171-Gly, Aal-187-Val | |||||
| Fluoroquinolones | Inhibition of DNA gyrase | DNA gyrase | M. tuberculosis (2 in 7H10) | gyrA | DNA gyrase subunit A | Ala-90-Val, Asp-94-Gly/Tyr | OFFICIAL, 1990; Cheng et al., 2004; Brown-Elliott et al., 2012; Kasperbauer and De Groote, 2015; Philley and Griffith, 2015 |
| M. kansasii (2) | gyrB | DNA gyrase subunit B | Asn-533-Thr | ||||
| RGM (4) | |||||||
| P-aminosalicylicacid (PAS) | Inhibition of folate synthesis | Thymidylate synthase, Dihydrofolate synthase, Dihydrofolate reductases | M. tuberculosis (2 in 7H10) | thyA | Thymidylate synthase | Thr-202-Ala, Val-261-Gly | Mathys et al., 2009; Da Silva and Palomino, 2011; Zheng et al., 2013; Zhao et al., 2014; Zhang X. et al., 2015 |
| folC | Dihydrofolate synthase | Glu-153-Aal, Asn-73-Ser | |||||
| ribD | Dihydrofolate reductases | G-11-A SNP | |||||
| Cycloserine | Inhibition of peptidoglycan synthesis | Alanine racemase, D-Alanine-D-alanine ligase, D-serine/L- and D-alanine/glycine/D-cycloserine proton symporter, L-alanine dehydrogenase | M. tuberculosis (5–10 in BACTEC) | alr | Alanine racemase | G-10-T SNP | Cáceres et al., 1997; Pelayo et al., 2009; Da Silva and Palomino, 2011; Chen et al., 2012; Gu et al., 2016 |
| ddl | D-Alanine-D-alanine ligase | – | |||||
| cycA Ald | D-serine/L- and D-alanine/glycine/D-cycloserine proton symporter | Gly-122-Ser | |||||
| L-alanine dehydrogenase | |||||||
| Macrolide- ketolide | Inhibition of protein synthesis | 50S ribosomal subunit | M. avium (8–16 in BACTEC) | rrl | 23S ribosomal RNA | A-2058-T, A-2059-C SNPs | Meier et al., 1994; Da Silva and Palomino, 2011; Philley and Griffith, 2015 |
| Clofazimine | Interfering with redox | NADH dehydrogenase | M. tuberculosis (1) | rv0678 | Transcriptional regulator | G193 deletion, C-466-T SNPs | Hartkoorn et al., 2014; Zhang S. et al., 2015 |
| Cycling, causing membrane destabilization and production of reactive oxygen species | rv2535c rv1979c | Peptidase Permease | G-265-T SNP T-1052-C SNP | ||||
| Oxazolidinones (Linezolid, Sutezolid [PNU-100480] and AZD5847 | Inhibition of protein synthesis | 50S ribosomal subunit | M. tuberculosis (4–8) | rrl rplC | 23S ribosomal rRNA 50S ribosomal protein L3 | G-2061-T, G-2576-T, G-2270-T T-460-C | Hillemann et al., 2008; Williams et al., 2009; Balasubramanian et al., 2014 |
| B-Lactams (In combination with belactamase inhibitor) | Inhibition of peptidoglycan synthesis | Transpeptidases | M. tuberculosis (NR) RGM (128) | blaC ponA Pbp | beta-lactamase Penicillin-binding Proteins Penicillin-binding proteins | – – – | Fattorini et al., 1992; Hugonnet and Blanchard, 2007; Brown-Elliott et al., 2012; Wivagg et al., 2014 |
| Tetracyclines and glycylcyclines | Inhibition of protein synthesis | 30S ribosomal subunit | RGM (8–16) | 16S rRNA gene | 16S rRNA | – | Brown-Elliott et al., 2012; Kasperbauer and De Groote, 2015 |
| Trimethoprim and sulfonamides | Inhibition of folate synthesis | Dihydrofolate reductase, Dihydropteroate synthetase | RGM (64) | dfrA sulI and folP1 | Dihydrofolate reductase Dihydropteroate synthetase | – | Brown-Elliott et al., 2012; Kasperbauer and De Groote, 2015 |
| Bedaquiline (TMC207) | Inhibition of ATP synthesis | ATP synthase | M. tuberculosis (0.25) | atpE | ATP synthase | Ala-63-Pro, Ile-66-Met | Andries et al., 2005; Segala et al., 2012 |
| Nitroimidazoles (PA-824 [Pretomanid] and OPC-67683 [Delamanid]) | Inhibition of cell wall lipid and protein synthesis | Dehydrogenase, Nitroreductase | M. tuberculosis (0.5) | Rv0407 Rv3547 | Dehydrogenase Nitroreductase | – – | Stover et al., 2000; Matsumoto et al., 2006; Rivers and Mancera, 2008 |
| SQ109 | Inhibition of lipid synthesis | Mycolic acids | M. tuberculosis (0.5) | mmpL3 | Membrane transporter | – | Protopopova et al., 2005; Tahlan et al., 2012 |
| Phenothiazines (Thioridazine and Chlorpromazine) | Inhibition of calcium transport, inhibition of type II NADH | – | M. tuberculosis (1–32) | – | – | – | Ordway et al., 2003; Martins et al., 2008 |
| Benzothiazinones (BTZ043) | Inhibition of cell wall arabinans synthesis | Nitroreductase, | M. tuberculosis (6) | nfnB dprE1 | Nitroreductase | – | Makarov et al., 2009; Manina et al., 2010 |
| Decaprenylphosphoryl epimerase | Decaprenylphosphoryl epimerase | – | |||||
| NAS-21 and NAS-91 | Inhibition of mycolic acid synthesis | FAS-II dehydratase | M. tuberculosis (NR) | rv0636 | FAS-II dehydratase | – | Gratraud et al., 2008 |
RGM, rapidly growing mycobacteria; SNP, single nucleotide polymorphism; NR, not reported.