Whole-Genome Sequence Analysis to Assess Mutations in Efflux Pumps in Mycobacterium tuberculosis: The Influence in Drug Resistance
Abstract
:1. Introduction
2. Materials and Methods
2.1. M. tuberculosis Genome and Database Construction
2.2. Bioinformatics Analysis
2.3. Statistical Analysis and Identification of Specific Variations in the Groups
3. Results
3.1. Characteristics of the Genomes Included in This Study
3.2. Sublineages Identified
3.3. Characterization of Variants and SNPs in the EPGs
3.4. Characterization of Variants and SNPs in Efflux Pump Genes Associated with Sublineages
3.5. Efflux Pump Genes Variants in TB Genomes from Individuals with TB Drug Resistance and T2DM
4. Discussion
5. Conclusions
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
References
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Locus (Gene) | Number of Genomes with Changes | No. of Changes | Position | Change | Frequency |
---|---|---|---|---|---|
Rv1145 (mmpL13a) | 101 | 4 | 1273071 | S217P | 98 |
Rv1461 | 84 | 9 | 1648620 | M544I | 78 |
Rv2994 | 97 | 5 | 3351926 | S220P | 75 |
Rv1557 (mmpL6) | 78 | 4 | 1762615 | A291V | 75 |
Rv2059 | 75 | 14 | 2315748 | D192A | 57 |
Rv0202c (mmpL11) | 72 | 13 | 239059 | R745Q | 57 |
Rv1967 (mce3B) | 82 | 11 | 2211600 | Q334E | 49 |
Rv0173 (lprK) | 56 | 7 | 204630 | R189Q | 39 |
Rv0194 | 53 | 15 | 227286 | V137M | 25 |
Rv0450c (mmpL4) | 53 | 11 | 541262 | V77A | 39 |
Sublineage | Locus (Gene) | Position | Change | Frequency |
---|---|---|---|---|
4.1.1.1-3 | Rv2994 | 3352244 | T326A | 13 |
Rv0783c (emrB) | 877224 | G406V | 11 | |
Rv0987 | 1102788 | V83F | 11 | |
Rv0507 (mmpL2) | 599165 | E656A | 15 | |
4.2.1 | Rv1819c (bacA) | 2063911 | I273T | 47 |
Rv0172 | 202675 | I67T | 47 | |
Rv3783 (rfbD) | 4230033 | V259A | 47 | |
Rv2059 | 2316510 | G446D | 47 | |
Rv2059 | 2315669 | V166I | 47 | |
Rv3498c | 3917305 | V232F | 47 | |
Rv3044 (fecB) | 3406045 | A304T | 47 | |
4.3.1 | Rv0592 (mce2D) | 691309 | S270N | 12 |
4.3.2 | Rv2398c (cysW) | 2695094 | A236P | 9 |
4.3.3 | Rv1668c | 1895174 | D57N | 71 |
4.3.4.1-2 | Rv2326c | 2599821 | A43S | 17 |
Rv0933 (pstB) | 1041445 | T61M | 17 | |
Rv1877 | 2126366 | V155L | 17 | |
Rv1672 | 197047 | M63V | 6 | |
Rv1967 (mce3B) | 2210740 | N47T | 6 | |
4.3.4.2 | Rv0037c | 40162 | M347I | 11 |
4.4.1.1-2 | Rv0987 | 1105102 | E854A | 13 |
Rv0987 | 1103786 | L415F | 13 | |
Rv1522c (mmpL12) | 1715531 | S694R | 10 | |
Rv1619 | 1819488 | R305Q | 13 | |
Rv1968 (mce3C) | 2211714 | Y30C | 10 | |
Rv0402c (mmpL1) | 482418 | G272R | 10 | |
4.10 | Rv0930 (pstA1) | 1037012 | T5M | 101 |
Rv2688c | 3005185 | T156P | 101 | |
Rv2398c (cysW) | 2695378 | A141G | 101 |
Locus (Gene) | Position | Change | Sensitive | Resistant | p-Value | ||
---|---|---|---|---|---|---|---|
Frequency (N = 223) | % | Frequency (N = 176) | % | ||||
Resistant isolates | |||||||
Rv0073 | 81990 | N105K | 4 | 1.8 | 35 | 20.0 | 0.000 |
Rv0171 (mce1C) | 202279 | P450T | 0 | 0 | 9 | 5.1 | 0.001 |
Rv0173 (lprK) | 204489 | L142S | 0 | 0 | 10 | 5.7 | 0.000 |
Rv0173 (lprK) | 204630 | R189Q | 4 | 1.8 | 35 | 20.0 | 0.000 |
Rv0206c (mmpL3) | 245080 | G747R | 0 | 0 | 9 | 5.1 | 0.001 |
Rv0411c (glnH) | 497682 | V207L | 4 | 1.8 | 35 | 20.0 | 0.000 |
Rv0435c | 524080 | A152P | 0 | 0 | 10 | 5.7 | 0.000 |
Rv0450c (mmpL4) | 541262 | V77A | 4 | 1.8 | 35 | 20.0 | 0.000 |
Rv0587 | 685336 | V70L | 0 | 0 | 10 | 5.7 | 0.000 |
Rv0676c (mmpL5) | 778107 | S125C | 0 | 0 | 5 | 2.8 | 0.016 |
Rv0783c (emrB) | 877011 | R477Q | 0 | 0 | 9 | 5.1 | 0.001 |
Rv1522c (mmpL12) | 1715219 | E798D | 0 | 0 | 5 | 2.8 | 0.016 |
Rv1619 | 1819507 | E311D | 0 | 0 | 9 | 5.1 | 0.001 |
Rv1667c | 1893672 | G187R | 0 | 0 | 9 | 5.1 | 0.001 |
Rv1966 (mce3A) | 2209807 | P161S | 12 | 5.4 | 38 | 21.6 | 0.000 |
Rv1967 (mce3B) | 2211600 | Q334E | 12 | 5.4 | 37 | 21 | 0.000 |
Rv2038c | 2284636 | L54W | 0 | 0 | 30 | 17 | 0.000 |
Rv2942 (mmpL7) | 3287806 | L913F | 0 | 0 | 10 | 5.7 | 0.000 |
Rv3758c (proV) | 4203468 | V317A | 0 | 0 | 5 | 2.8 | 0.016 |
Sensitive isolates | |||||||
Rv0194 | 227133 | H86Y | 7 | 3.1 | 0 | 0 | 0.019 |
Rv0194 | 227286 | V137M | 15 | 6.7 | 0 | 0 | 0.000 |
Rv0933 (pstB) | 1042067 | D268E | 15 | 6.7 | 0 | 0 | 0.000 |
Rv1145 | 1273071 | S217P | 64 | 29 | 34 | 19 | 0.035 |
Rv1971 (mce3F) | 2216394 | T380P | 15 | 6.7 | 0 | 0 | 0.000 |
Rv2329c (narK1) | 2602760 | M234I | 7 | 3.1 | 0 | 0 | 0.019 |
Rv3041c | 3401501 | R140C | 11 | 4.9 | 1 | 0.6 | 0.015 |
Rv3783 (rfbD) | 4229625 | V123A | 14 | 6.3 | 0 | 0 | 0.000 |
Locus (Gene) | Position | Change | Host with TB | Host with TB-T2DM | ° p-Value | ||
---|---|---|---|---|---|---|---|
N = 224 | % | (N = 175) | % | ||||
TB-T2DM dominance | |||||||
Rv0170 (mce1B) | 200154 | R85C | 1 | 0.4 | 6 | 3.4 | 0.047 |
Rv0171 (mce1C) | 202279 | P450T * | 2 | 0.9 | 7 | 4 | 0.046 |
Rv0206c (mmpL3) | 244911 | P803R | 0 | 0 | 8 | 4.6 | 0.001 |
Rv0206c (mmpL3) | 245080 | G747R * | 2 | 0.9 | 7 | 4 | 0.046 |
Rv0265c | 317392 | G38S | 0 | 0 | 4 | 2.3 | 0.036 |
Rv0587 (yrbE2A) | 685336 | V70L * | 2 | 0.9 | 8 | 4.6 | 0.025 |
Rv0783c (emrB) | 877011 | R477Q * | 2 | 0.9 | 7 | 4 | 0.046 |
Rv0986 | 1101898 | D32E | 0 | 0 | 5 | 2.9 | 0.016 |
Rv1146 (mmpL13b) | 1274703 | L450S | 1 | 0.4 | 6 | 3.4 | 0.047 |
Rv1273c | 1423383 | A223D | 0 | 0 | 5 | 2.9 | 0.016 |
Rv1619 | 1819507 | E311D * | 2 | 0.9 | 7 | 4 | 0.046 |
Rv1667c | 1893672 | G187R * | 2 | 0.9 | 7 | 4 | 0.038 |
Rv1843c (guaB1) | 2093455 | A82T | 0 | 0 | 5 | 2.9 | 0.016 |
Rv2041c | 2286715 | R378G | 0 | 0 | 5 | 2.9 | 0.016 |
Rv2265 | 2539687 | V330I | 0 | 0 | 6 | 3.4 | 0.007 |
Rv2339 (narK1) | 2617051 | M787V | 0 | 0 | 9 | 5.1 | 0.001 |
Rv2942 (mmpL7) | 3287806 | L913F * | 2 | 0.9 | 8 | 4.6 | 0.025 |
Rv3041c | 3401501 | R140C # | 2 | 0.9 | 10 | 5.7 | 0.007 |
Rv3823c (mmpL8) | 4291418 | L38V | 1 | 0.4 | 6 | 3.4 | 0.047 |
TB dominance | |||||||
Rv0073 | 81990 | N105K * | 32 | 14.3 | 7 | 4 | 0.001 |
Rv0173 (lprK) ** | 204630 | R189Q * | 32 | 14.3 | 7 | 4 | 0.001 |
Rv0194 ** | 227286 | V137M # | 15 | 6.7 | 0 | 0 | 0.000 |
Rv0202c (mmpL11) ** | 239059 | R745Q | 47 | 21 | 10 | 5.7 | 0.000 |
Rv0402c (mmpL1) | 481374 | R620G | 21 | 9.4 | 6 | 3.4 | 0.026 |
Rv0411c (glnH) | 497682 | V207L * | 32 | 14.3 | 7 | 4 | 0.001 |
Rv0450c (mmpL4) ** | 541262 | V77A * | 32 | 14.3 | 7 | 4 | 0.001 |
Rv0529 (ccsA) | 619969 | V27I | 24 | 10.7 | 6 | 3.4 | 0.007 |
Rv0676c (mmpL5) | 777451 | V344L | 8 | 3.6 | 0 | 0 | 0.011 |
Rv0933 (pstB) | 1042067 | D268E # | 15 | 6.7 | 0 | 0 | 0.000 |
Rv1145 (mmpL13a) ** | 1273071 | S217P # | 72 | 32.1 | 26 | 14.9 | 0.000 |
Rv1218c | 1361802 | P311Q | 8 | 3.6 | 0 | 0 | 0.011 |
Rv1557 (mmpL6) ** | 1762615 | A291V | 53 | 23.7 | 22 | 12.6 | 0.006 |
Rv1859 | 2107663 | H364Y | 9 | 4 | 0 | 0 | 0.006 |
Rv1966 (mce3A) | 2209807 | P161S | 43 | 19.2 | 7 | 4 | 0.000 |
Rv1967 (mce3) | 2211121 | T174M | 8 | 3.6 | 0 | 0 | 0.011 |
Rv1967 (mce3B) ** | 2211600 | Q334E | 42 | 18.8 | 7 | 4 | 0.000 |
Rv1971 (mce3F) | 2216394 | T380P # | 15 | 6.7 | 0 | 0 | 0.000 |
Rv2038c | 2284636 | L54W | 24 | 10.7 | 6 | 3.4 | 0.007 |
Rv2994 ** | 3351926 | S220P | 53 | 23.7 | 22 | 12.6 | 0.005 |
Rv3783 (rfbD) | 4229625 | V123A # | 14 | 6.3 | 0 | 0 | 0.000 |
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Chimal-Muñoz, M.; Pérez-Martínez, D.E.; Bermúdez Hernández, G.A.; Mejía-Ponce, P.M.; Licona-Cassani, C.; Muñiz-Salazar, R.; Montero, H.; Zenteno-Cuevas, R. Whole-Genome Sequence Analysis to Assess Mutations in Efflux Pumps in Mycobacterium tuberculosis: The Influence in Drug Resistance. Microorganisms 2025, 13, 1306. https://doi.org/10.3390/microorganisms13061306
Chimal-Muñoz M, Pérez-Martínez DE, Bermúdez Hernández GA, Mejía-Ponce PM, Licona-Cassani C, Muñiz-Salazar R, Montero H, Zenteno-Cuevas R. Whole-Genome Sequence Analysis to Assess Mutations in Efflux Pumps in Mycobacterium tuberculosis: The Influence in Drug Resistance. Microorganisms. 2025; 13(6):1306. https://doi.org/10.3390/microorganisms13061306
Chicago/Turabian StyleChimal-Muñoz, Miguel, Damián E. Pérez-Martínez, Gustavo A. Bermúdez Hernández, Paulina M. Mejía-Ponce, Cuauhtémoc Licona-Cassani, Raquel Muñiz-Salazar, Hilda Montero, and Roberto Zenteno-Cuevas. 2025. "Whole-Genome Sequence Analysis to Assess Mutations in Efflux Pumps in Mycobacterium tuberculosis: The Influence in Drug Resistance" Microorganisms 13, no. 6: 1306. https://doi.org/10.3390/microorganisms13061306
APA StyleChimal-Muñoz, M., Pérez-Martínez, D. E., Bermúdez Hernández, G. A., Mejía-Ponce, P. M., Licona-Cassani, C., Muñiz-Salazar, R., Montero, H., & Zenteno-Cuevas, R. (2025). Whole-Genome Sequence Analysis to Assess Mutations in Efflux Pumps in Mycobacterium tuberculosis: The Influence in Drug Resistance. Microorganisms, 13(6), 1306. https://doi.org/10.3390/microorganisms13061306