Abstract
A comprehensive literature search was conducted to obtain previously published resistance associated mutations for bedaquiline, clofazimine and linezolid for Mycobacterium tuberculosis. Where possible, mutation frequencies for these three drugs were also identified. This catalog of previously published mutations could serve as a reference for comparing mutations associated with either in vitro or clinical resistant mutants. The usage of these data was seen in our study relating to approaches for resistance mutant creation (in vitro approaches for generation of Mycobacterium tuberculosis mutants resistant to bedaquiline, clofazimine or linezolid and identification of associated genetic variants (Ismail et al., 2018 in press). Previously published mutations for clofazimine were described in the rv0678 and rv1979c genes, for bedaquiline in atpE, rv0678 and rv2535c (pepQ) genes and for linezolid in the rplC and rrl genes.
Specifications table
| Subject area | Biology |
|---|---|
| More specific subject area | Microbiology |
| Type of data | Tables |
| How data was acquired | Literature search for mutation frequencies and genetic variants related to bedaquiline, clofazimine and linezolid resistance |
| Data format | Filtered |
| Experimental factors | Published articles regarding bedaquiline, clofazimine and linezolid resistant isolates and associated mutations |
| Experimental features | Previously published mutations in rv0678, rv1979c, rv2535c, atpE, rplC and rrl genes and mutation frequencies associated with either bedaquiline-, clofazimine- or linezolid-resistant M. tuberculosis |
| Data source location | South Africa |
| Data accessibility | Data is included in this article and accessible in related referenced articles |
| Related research article | Ismail, N., Omar, S.V., Ismail, N.A., Peters, R.P.H. (2018). in vitro approaches for generation of Mycobacterium tuberculosis mutants resistant to bedaquiline, clofazimine or linezolid and identification of associated genetic variants, JMM (In press) |
Value of the data
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The data pertaining to genetic variants for bedaquiline, clofazimine and linezolid resistance are vital for understanding drug mechanisms of action.
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A catalog such as this may prevent data replication and serve as a comparator or reference for other studies related to resistance-associated mutation.
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The combined data of the resistance-associated variants could provide a starting point for the design of molecular susceptibility tests.
1. Data
The data in this article includes previously published mutations identified in both in vitro (Tables 1 and 3) as well as clinical isolates (Tables 2 and 4) associated with bedaquiline, clofazimine or linezolid resistance. Data were filtered according to the type of mutation identified and the gene in which the mutation occurred. Where available the in vitro approach used to generate the mutant, any information around the strain the mutants were derived from, the mutant MIC value as well as the article from which the data was derived from were included in the data. As bedaquiline- and clofazimine-resistant isolates tend to harbor rv0678 mutations, data for these mutants were presented together. The final data table (Table 5) describes previously published mutation frequencies. A diversity of mutations were identified in the rv0678 gene and were scattered along the gene. For the atpE gene, hotspots have been identified at positions 28 and 63. Mutations in the rplC and rrl target genes appear to be associated with either high or low-level linezolid resistance respectively. Four mutations in rv2535c were identified in in vivo bedaquiline and clofazimine resistant isolates. Rv1979c mutations were found in clinical pre-XDR and XDR isolates.
Table 1.
Catalog of previously published mutations from bedaquiline- and clofazimine-resistant in vitro and in vivo isolates.
| Mutation |
Approach | Notes | MIC (µg/mL) |
Refs. | |||
|---|---|---|---|---|---|---|---|
| rv0678 | atpE | rv2535c | BDQ | CFZ | |||
| – | G187C | – | Serial Passage | Fully susceptible strain | >8 | – | [1] |
| T461C | A83G | Isoniazid-resistant strain | >8 | ||||
| 201_206del | A83C | Kanamycin-resistant strain | >8 | ||||
| – | G183T | Pyrazinamide-resistant strain | >8 | ||||
| A83G | |||||||
| A63T | A83G | Rifampicin-resistant strain | >8 | ||||
| G74A | – | Fully susceptible strain | – | 4 | |||
| T131C | Isoniazid-resistant strain | >4 | |||||
| T407C | Kanamycin-resistant strain | 4 | |||||
| C204A | Pyrazinamide-resistant strain | >4 | |||||
| T131C | Rifampicin-resistant strain | 4 | |||||
| – | A83T | – | Spontaneous | Fully susceptible strain | >8 | – | |
| C403G | Pyrazinamide-resistant strain | 4 | |||||
| – | A83G | Pyrazinamide-resistant strain | 8 | ||||
| – | G187C | Pyrazinamide-resistant strain | >8 | ||||
| 193delG | – | Fully susceptible strain | – | 2 | |||
| 193delG | Fully susceptible strain | 4 | |||||
| A65T | Fully susceptible strain | 4 | |||||
| T407C | Pyrazinamide-resistant strain | 1 | |||||
| C214T | Pyrazinamide-resistant strain | 2 | |||||
| G137A | Pyrazinamide-resistant strain | 4 | |||||
| A97G | |||||||
| – | – | CinArg271 | in vivo | Mice treated with BDQ only | 0.12 | 0.5-1 | [2] |
| +CinAla14 | Mice treated with BDQ and CFZ | 0.12 | |||||
| +CinAla14 | 0.12 | ||||||
| L44P | 0.12 | ||||||
| A413G | WT | – | in vitro mutants | Mutants derived from H37Rv | 0.25 | – | [3], [5] |
| G281A | WT | 0.5 | |||||
| A202G | WT | Mutants derived from MDR M. tuberculosis clinical strain | 0.5 | ||||
| Ins G 192-193 | I66M | 4 | |||||
| IS6110 nt 272 | WT | 1 | |||||
| Ins A 38–39 | WT | 1 | |||||
| – | A95T | – | Mutagenesis | M. smegmatis | – | – | [4], [5] |
| – | C198G | – | Spontaneous | M. tuberculosis | – | – | [6] |
| G187C | – | – | |||||
| – | G183T | – | Spontaneous | 2 isolates from MDR strain | 0.24–0.48 | – | [7] |
| G187C | 3 isolates from MDR strain | 0.9–3.84 | |||||
| A83T | 1 isolate from MDR strain | 0.48 | |||||
| C198G | 1 isolate from MDR strain | 0.48 | |||||
| A83G | 1 isolate from WT strain | 0.3 | |||||
| G183T | 3 isolates from WT strain | 0.48–0.96 | |||||
| G187C | 4 isolates from WT strain | 0.24–0.9 | |||||
| – | G187C | – | Spontaneous | – | 4–8x MIC | – | [8] |
| A95T | 4–8x MIC | ||||||
| C189A | – | – | Spontaneous | – | 0.5 | 1.25 | [9] |
| C400T | 0.5 | 1.25 | |||||
| G193 deletion | – | – | Spontaneous | 23 isolates | – | All ≤1 | [10] |
| G193 insertion | 21 isolates | ||||||
| C466T | 11 isolates | ||||||
| C364 insertion | 5 isolates | ||||||
| A202G | 5 isolates | ||||||
| T2C | 2 isolates | ||||||
| G58T | 1 isolate | ||||||
| C107T | 1 isolate | ||||||
| G125A | 1 isolate | ||||||
| T29 insertion | 1 isolate | ||||||
| C98A | 1 isolate | ||||||
| T128G | 1 isolate | ||||||
| G137A | 2 isolate | ||||||
| A152G | 1 isolate | ||||||
| C158T | 1 isolate | ||||||
| C176T | 1 isolate | ||||||
| G188A | 1 isolate | ||||||
| G194A | 2 isolates | ||||||
| G197T | 1 isolate | ||||||
| C226T | 1 isolate | ||||||
| C251A | 1 isolate | ||||||
| G266T | 1 isolate | ||||||
| G269C | 1 isolate | ||||||
| A292 deletion | 1 isolate | ||||||
| G304A | 1 isolate | ||||||
| C305T | 2 isolates | ||||||
| T341C | 1 isolate | ||||||
| T365C | 1 isolate | ||||||
| CGCTGGGC371–378 deletion | 1 isolate | ||||||
| CG444–445 deletion | 1 isolate | ||||||
| G193 insertion | 1 isolate | ||||||
| – | 3 isolates | ||||||
| – | G265T | 1 isolate | |||||
| – | A63P | – | – | Mutants from H37Rv reference strain | 4 | – | [11] |
| D28G | Mutants from M. tuberculosis clinical isolates | 0.5 | |||||
| E61D | 0.5 | ||||||
| L59V | 0.25 | ||||||
| I66M | 1 | ||||||
Mutations described in rv0678, atpE and rv2535c genes. A dash (–) is used to indicate where no data is available. WT-wild type, no variants detected. BDQ-Bedaquiline. CFZ-Clofazimine.
Table 3.
Catalog of previously published mutations from linezolid-resistant in vitro mutants.
|
Mutation |
Approach | Note | MIC value (µg/ml) | Refs. | |
|---|---|---|---|---|---|
| rrl | rplC | ||||
| – | T460C | Serial passage | Isoniazid-resistant strain | >8 | [1] |
| T460C | Kanamycin-resistant strain | 8 | |||
| T460C | Pyrazinamide-resistant strain | >8 | |||
| T460C | Rifampicin-resistant strain | 8 | |||
| – | T460C | Spontaneous | Fully susceptible strain | >8 | |
| G2270C | – | Pyrazinamide-resistant strain (13 mutants derived) | 4 | ||
| A2810C | – | 4 | |||
| – | T460C | 8 to >8 | |||
| G2061T | – | Spontaneous | 4 isolates | 32 | [23], [24] |
| G2576T | – | 1 isolate | 16 | ||
| none | – | 5 isolates | 4-8 | ||
| C2848A | – | Serial passage | 17 of 32 had rrl mutations, remainder had rplC | – | [25] |
| A2810T | – | ||||
| G2270C | – | ||||
| G2270T | – | ||||
| G2746A | – | ||||
| – | T460C | ||||
| – | T460C | Spontaneous | 3 in vitro mutants selected for sequencing | 16 | [26] |
| T460C | 32 | ||||
| G2270T | – | 8 | |||
| G2814T | – | Spontaneous | 4 isolates | 25–50 | [27] |
| – | T460C | 12 isolates | 50 | ||
| G2299T | – | 7 isolates | 65–156 | ||
| A2689T | – | 1 isolate | 60 | ||
| G2814T | – | 4 isolates | 94 | ||
Mutations described in rrl and rplC genes. A dash (–) is used to indicate where data was not available.
Table 2.
Catalog of previously published mutations from bedaquiline- and clofazimine-resistant clinical isolates.
|
Mutation |
Notes |
MIC (µg/ml) |
Refs. | |||
|---|---|---|---|---|---|---|
| rv0678 | atpE | rv1979c | BDQ | CFZ | ||
| T124C | – | – | Clinical strains from BDQ trial | 0.25 | [3] | |
| A97C | 0.5 | – | ||||
| C107T | 0.5 | |||||
| Del C 212 | 0.5 | |||||
| Ins IS6110 nt 272 | 0.5 | |||||
| Ins C 141–142 | 0.25 | |||||
| 2T>C | WT | – | fMet1Ala-relapse isolate after | 0.5 | 4 | [12], [13], [14] |
| BDQ compassionate use | ||||||
| T437C | WT | WT | XDR | 0.78 | 1.2 | [15] |
| G5T | WT | WT | Pre-XDR | 0.73 | 4 | |
| C158T | WT | WT | Pre-XDR | 0.39 | 2.09 | |
| T350G | WT | WT | XDR | 1.54 | 4.16 | |
| WT | WT | A155C | Pre-XDR | 0.08 | 1.2 | |
| Del gg 18–19 | – | – | MDR isolates | 0.5 | – | [16] |
| Ins G140 | 0.25 | |||||
| M139T | 0.25 | |||||
| 198–199 Ins G | – | – | Mix: WT + rv0678 mutant | 0.24;0.48;1 | – | [17], [18] |
| 274–275 Ins A | 1 | |||||
| C148T, A187G | intergenic mutation, rv0678 mutant | 0.48 | ||||
| G334C, (-13) Ins IS6110 | 0.48 | |||||
| C185T | 0.48 | |||||
| C155T | 0.48 | |||||
| C176T | 0.48 | |||||
| 224–225 Ins A | 0.24 | |||||
| T(-44)C | 0.24 | |||||
| A263G | Mix: WT + rv0678 mutant | 0.12 | ||||
| T116C | 0.12 | |||||
| T124C | Mix: WT + rv0678 mutant (silent mutation) | 0.12 | ||||
| C45T | 0.12 | |||||
| G256A | 0.12 | |||||
| [Ins139g] | WT | – | 0.12–0.25 | – | [19] | |
| L142R | WT | Baseline and post-treatment BDQ isolates from BDQ clinical trials | 0.25 | |||
| L142R | A63V | 0.25–1 | ||||
| [Del198G] [Del212C] [G233C, G78A] | WT | 0.12 | ||||
| [G66W] [Del198G] [Ins263A] [Del435T] | WT | 0.12 | ||||
| [Del198G] [Ins466C] | WT | 0.25 | ||||
| [Del435T] | WT | 0.25 | ||||
| [E113K] [Del198G] [Del435T] | WT | 0.25 | ||||
| [Del435T] | WT | 0.25 | ||||
| G121E | WT | 0.25 | ||||
| [L40S] [Del291C] [Ins386C] | WT | 0.25 | ||||
| Del291C | WT | 0.25 | ||||
| [S53P] [Del198G] [Del336C] | WT | 0.25 | ||||
| M23L | WT | 0.06 | ||||
| M23L Ins142C | WT | 0.12 | ||||
| M23L [Ins142C] [Ins419G] | WT | 0.12 | ||||
| M23L Ins419g | WT | 0.12 | ||||
| [Del19G] [E49stop] [Del198G] [Ins468GA] | WT | 0.12 | ||||
| -[V85A] [R135W] | WT | 0.12 | ||||
| V85A | WT | 0.12 | ||||
| Ins44A | WT | 0.06 | ||||
| [Ins144C] | WT | 0.12–0.25 | ||||
| Ins421G | WT | 0.12–0.25 | ||||
| Del32G | WT | 0.06; 0.25 | ||||
| [Y26stop] [L122P] | WT | 0.12 | ||||
| L122P | WT | 0.12 | ||||
| [Del214C] [Del198G] | WT | 0.06 | ||||
| [F79S] [Ins137G] | WT | 0.12 | ||||
| [Del19G] [Del198G] | WT | 0.12 | ||||
| A98V | WT | 0.12–0.25 | ||||
| WT | D28N | 0.12 | ||||
| [Ins139G] + [Ins318CG] | WT | 0.12 | ||||
| [Del274–283] [Ins139TG] | WT | 0.12 | ||||
| [C46R] [Ins139TG] [L40S] | WT | 0.12 | ||||
| Ser53Pro | WT | – | 2 XDR isolates | 0.5 | 2–4 | [20] |
| Ser53Leu | 1 XDR isolate | 0.25 | 2 | |||
| Tyr157Asp | 1 XDR isolate | 0.125 | 2 | |||
| WT | 1 XDR isolate | 0.5 | 2 | |||
| WT | WT | G1226A | 3 XDR isolates: Culture negative at 6 months | 0.25–1 (MGIT) 0.06–0.125 (BMD) | 0.5 (MGIT) | [21] |
| 136_137insG | G1226A | XDR: : Culture positive at 6 months | 2 (MGIT) 0.25 (BMD) | 0.5 (MGIT) | ||
| 138_139insG | G1226A | XDR: Culture positive at 6 months | 2 (MGIT) 0.5 (BMD) | 2 (MGIT) | ||
| 141_142insC | G1226A | 2 XDR isolates: Culture positive at 6 months | 4 (MGIT) 0.25–0.5 (BMD) | 0.5–1 (MGIT) | ||
| T200G | G1226A | XDR: Culture positive at 6 months | 4 (MGIT) 0.5 (BMD) | 2 (MGIT) | ||
| 345delG | G1226A | XDR: Culture positive at 6 months | 4 (MGIT) 0.5 (BMD) | 1 (MGIT) | ||
| -11C>A | WT | – | Fully susceptible clinical isolate | 0.016 | – | [22] |
| D5G | WT | Fully susceptible clinical isolate | 0.016 | |||
| M23V | WT | STR resistant clinical isolate | 0.063 | |||
| D47fs | WT | XDR clinical isolate | 0.5 | |||
| E55D | WT | Fully susceptible clinical isolate | 0.063 | |||
| G87R | WT | Fully susceptible clinical isolate | 0.063 | |||
| R96Q | WT | INH resistant | 0.25 | |||
| L117R | WT | Fully susceptible clinical isolate | 0.016 | |||
| WT | -53G>A | Fully susceptible clinical isolate | 0.125 | |||
| WT | -72T>C | RIF and INH resistant clinical isolate | 8 | |||
| WT | -138T>C | 3 RIF and INH resistant clinical isolates | 0.031 | |||
| WT | 183G>A | Fully susceptible clinical isolate | 0.063 | |||
| WT | I66V | Fully susceptible clinical isolate | 0.125 | |||
Mutations described in rv0678, atpE and rv1979c genes. A dash (–) is used to indicate where no data was available. WT-wild type, no variants detected. MGIT- MGIT960 platform used to determine MIC. BMD- Broth Micro Dilution method used to determine MIC. BDQ-Bedaquiline. CFZ-Clofazimine.
Table 4.
Catalog of previously published mutations from linezolid-resistant clinical isolates.
|
Mutation |
Note | MIC value (µg/ml) | Refs. | |
|---|---|---|---|---|
| rrl | rplC | |||
| WT | – | No mutations in rplD, rplV, whiB7, rrl, erm-37 | 8 (3 strains) | [23] |
| WT | 4 (1 strain) | |||
| – | T460C | 2 resistant, 3 acquired resistance during treatment | 4–16 | [24] |
| G2447T | – | acquired resistance during treatment | 16 | |
| – | T460C | – | 2 | [28] |
| – | T460C | 0.5 | ||
| – | T460C | 4 | ||
| G2576T | – | 4 | ||
| G2576T | – | 4 | ||
| – | T460C | 8 isolates | – | [19] |
| G2814T | – | 1 isolate | ||
| C1921T | – | 1 isolate | ||
| G2294A | – | 1 isolate acquired resistance during treatment | ||
| G2576T | – | 1 MDR-TB isolate | 4 | [13] |
| A2572C | – | |||
| – | T460C | 2 XDR-TB isolates | 4–16 | [12] |
Mutations described in rrl and rplC genes. A dash (–) is used to indicate where data was not available. WT- wild type, no variants detected.
Table 5.
Mutation frequencies and selection concentrations for bedaquiline-, clofazimine- and linezolid-resistant spontaneous mutants from previously published studies.
| Drug | Conc (µg/ml) | Strain | Mutation frequency | Refs. |
|---|---|---|---|---|
| Bedaquiline | 0.12 | Fully susceptible M. tuberculosis | 5 × 10–7 | [8] |
| 0.12 | M. smegmatis | 2 × 10–8 | ||
| 0.24 | Fully susceptible M. tuberculosis | 5 × 10–8 | ||
| 0.24 | M. smegmatis | 1 × 10–8 | ||
| 0.03-0.05 | Fully susceptible M. tuberculosis | 1 × 10–8 | [11] | |
| Clinical M. tuberculosis | 5 × 10–8 | |||
| Clinical M. tuberculosis | 1 × 10–8 | |||
| Clinical M. tuberculosis | 1 × 10–8 | |||
| 0.015-0.5 | Clinical strain M. fortuitum | 1.5 × 10–8 | ||
| 0.25-8 | Clinical strain M. abscessus | 1.5 × 10–8 | ||
| 1 | Fully susceptible M. tuberculosis | 6 × 10–9 | [1] | |
| Pyrazinamide-resistant M. tuberculosis | 4 × 10−7 | |||
| Clofazimine | 0.25 | Fully susceptible M. tuberculosis | 5 × 10−6 | [10] |
| 1 | Fully susceptible M. tuberculosis | 5 × 10−5 | [1] | |
| Pyrazinamide-resistant M. tuberculosis | 7 × 10−7 | |||
| Linezolid | – | Fully susceptible M. tuberculosis | 2 × 10−8 | [23] |
| – | Fully susceptible M. tuberculosis | 5 × 10−9 | ||
| 2 | Fully susceptible M. tuberculosis | 1 × 10−8 | [1] | |
| Pyrazinamide-resistant M. tuberculosis | 1 × 10−7 |
A dash (–) is used to indicate where data was not available.
2. Experimental design, materials and methods
A catalog was compiled of mutations observed for in vitro, in vivo and clinical M. tuberculosis strains resistant to bedaquiline, clofazimine and linezolid as reported in studies that were identified through a comprehensive literature search. This was done by searching for combinations of each drug (or drug class) together with terms like “resistant”, “resistance”, “mutant”, “mutations” as well as “Mycobacterium tuberculosis”. Related and citing articles were also reviewed. The articles were then analyzed on the basis of the approach used and the mutations documented. Mutations were delineated as arising from either in vivo or clinical and in vitro.
Acknowledgements
Nabila Ismail received PhD support from The National Research Fund, South Africa (SFH150723130071) and the University of Pretoria, South Africa.
Footnotes
Transparency data associated with this article can be found in the online version at https://doi.org/10.1016/j.dib.2018.09.057.
Transparency document. Supplementary material
Supplementary material
.
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