Differential Expression of Resistant and Efflux Pump Genes in MDR-TB Isolates

Author(s): Manaf AlMatar*, Işıl Var, Begüm Kayar, Fatih Köksal

Journal Name: Endocrine, Metabolic & Immune Disorders - Drug Targets
Formerly Current Drug Targets - Immune, Endocrine & Metabolic Disorders

Volume 20 , Issue 2 , 2020

Become EABM
Become Reviewer
Call for Editor

Graphical Abstract:


Background: Numerous investigations demonstrate efflux as a worldwide bacterial mode of action which contributes to the resistance of drugs. The activity of antibiotics, which subjects to efflux, can be improved by the combined usage of efflux inhibitors. However, the efflux role to the overall levels of antibiotic resistance of clinical M. tuberculosis isolates is inadequately comprehended and is still disregarded by many.

Methods: Here, we assessed the contribution of resistant genes associated with isoniazid (INH) and rifampin (R) resistance to the levels of drug resistance in the (27) clinical isolates of MDR-TB. Additionally, the role of the resistance for six putative drug efflux pump genes to the antibiotics was investigated. The level of katG expression was down-regulated in 24/27 (88.88%) of MDR-TB isolates. Of the 27 MDR-TB isolates, inhA, oxyR-ahpC, and rpoB showed either overexpression or up-regulation in 8 (29.62%), 4 (14.81 %), and 24 (88.88%), respectively. Moreover, the efflux pump genes drrA, drrB, efpA, Rv2459, Rv1634, and Rv1250 were overexpressed under INH/RIF plus fresh pomegranate juice (FPJ) stress signifying the efflux pumps contribution to the overall levels of the resistance of MDR-TB isolates.

Conclusion: These results displayed that the levels of drug resistance of MDR-TB clinical isolates are due to combination among drug efflux pump and the presence of mutations in target genes, a truth which is often ignored by the specialists of tuberculosis in favour of the almost undoubted significance of drug target- gene mutations for the resistance in M. tuberculosis.

Keywords: Mycobacterium tuberculosis, antituberculosis agents, efflux pumps, gene expression, RT-qPCR, drug resistance.

Feng, L-S.; Liu, M-L.; Wang, B.; Chai, Y.; Hao, X-Q.; Meng, S.; Guo, H-Y. Synthesis and in vitro antimycobacterial activity of balofloxacin ethylene isatin derivatives. Eur. J. Med. Chem., 2010, 45(8), 3407-3412.
[http://dx.doi.org/10.1016/j.ejmech.2010.04.027] [PMID: 20493593]
AlMatar, M.; AlMandeal, H.; Var, I.; Kayar, B.; Köksal, F. New drugs for the treatment of Mycobacterium tuberculosis infection. Biomed. Pharmacother., 2017, 91, 546-558.
[http://dx.doi.org/10.1016/j.biopha.2017.04.105] [PMID: 28482292]
Organization, W. H. Global tuberculosis report 2016., 2016.
AlMatar, M.; Makky, E.A.; Var, I.; Kayar, B.; Köksal, F. Novel compounds targeting InhA for TB therapy. Pharmacol. Rep., 2017.
[PMID: 29475004]
AlMatar, M.; Makky, E.A.; Yakıcı, G.; Var, I.; Kayar, B.; Köksal, F. Antimicrobial peptides as an alternative to anti-tuberculosis drugs. Pharmacol. Res., 2018, 128, 288-305.
[PMID: 29079429]
Viuda‐Martos, M.; Fernández‐López, J.; Pérez‐Álvarez, J. Pomegranate and its many functional components as related to human health: a review. Compr. Rev. Food Sci. Food Saf., 2010, 9, 635-654.
Wilson, T.M.; Collins, D.M. ahpC, a gene involved in isoniazid resistance of the Mycobacterium tuberculosis complex. Mol. Microbiol., 1996, 19(5), 1025-1034.
[http://dx.doi.org/10.1046/j.1365-2958.1996.449980.x] [PMID: 8830260]
Miesel, L.; Weisbrod, T.R.; Marcinkeviciene, J.A.; Bittman, R.; Jacobs, W.R. Jr NADH dehydrogenase defects confer isoniazid resistance and conditional lethality in Mycobacterium smegmatis. J. Bacteriol., 1998, 180(9), 2459-2467.
[PMID: 9573199]
Mdluli, K.; Slayden, R.A.; Zhu, Y.; Ramaswamy, S.; Pan, X.; Mead, D.; Crane, D.D.; Musser, J.M.; Barry, C.E. III Inhibition of a Mycobacterium tuberculosis β-ketoacyl ACP synthase by isoniazid. Science, 1998, 280(5369), 1607-1610.
[http://dx.doi.org/10.1126/science.280.5369.1607] [PMID: 9616124]
Telenti, A.; Imboden, P.; Marchesi, F.; Lowrie, D.; Cole, S.; Colston, M.J.; Matter, L.; Schopfer, K.; Bodmer, T. Detection of rifampicin-resistance mutations in Mycobacterium tuberculosis. Lancet, 1993, 341(8846), 647-650.
[http://dx.doi.org/10.1016/0140-6736(93)90417-F] [PMID: 8095569]
Siddiqi, N.; Das, R.; Pathak, N.; Banerjee, S.; Ahmed, N.; Katoch, V.M.; Hasnain, S.E. Mycobacterium tuberculosis isolate with a distinct genomic identity overexpresses a tap-like efflux pump. Infection, 2004, 32(2), 109-111.
[http://dx.doi.org/10.1007/s15010-004-3097-x] [PMID: 15057575]
Ramón-García, S.; Martín, C.; Thompson, C.J.; Aínsa, J.A. Role of the Mycobacterium tuberculosis P55 efflux pump in intrinsic drug resistance, oxidative stress responses, and growth. Antimicrob. Agents Chemother., 2009, 53(9), 3675-3682.
[http://dx.doi.org/10.1128/AAC.00550-09] [PMID: 19564371]
Ramón-García, S.; Mick, V.; Dainese, E.; Martín, C.; Thompson, C. J.; De Rossi, E.; Manganelli, R.; Aínsa, J. A. Functional and genetic characterization of the tap efflux pump in Mycobacterium bovis BCG. Antimicrobial agents and chemotherapy, 2012, AAC 05946-11
Machado, D.; Couto, I.; Perdigão, J.; Rodrigues, L.; Portugal, I.; Baptista, P.; Veigas, B.; Amaral, L.; Viveiros, M. Contribution of efflux to the emergence of isoniazid and multidrug resistance in Mycobacterium tuberculosis. PLoS One, 2012, 7(4)e34538
[http://dx.doi.org/10.1371/journal.pone.0034538] [PMID: 22493700]
Schmalstieg, A.M.; Srivastava, S.; Belkaya, S.; Deshpande, D.; Meek, C.; Leff, R.; van Oers, N.S.; Gumbo, T. The antibioticresistance arrow of time: efflux pump induction is a general first step in the evolution of mycobacterial drug-resistance. The antibiotic- resistance arrow of time: efflux pump induction is a general first step in the evolution of mycobacterial drug-resistance, 2012, , 05546-11. AAC.
Livak, K. J.; Schmittgen, T. D. Analysis of relative gene expression data using real-time quantitative PCR and the 2− ΔΔCT method. methods, 2001, 25, 402.
DeMarco, C.E.; Cushing, L.A.; Frempong-Manso, E.; Seo, S.M.; Jaravaza, T.A.; Kaatz, G.W. Efflux-related resistance to norfloxacin, dyes, and biocides in bloodstream isolates of Staphylococcus aureus. Antimicrob. Agents Chemother., 2007, 51(9), 3235-3239.
[http://dx.doi.org/10.1128/AAC.00430-07] [PMID: 17576828]
Rodrigues, L.; Machado, D.; Couto, I.; Amaral, L.; Viveiros, M. Contribution of efflux activity to isoniazid resistance in the Mycobacterium tuberculosis complex. Infect. Genet. Evol., 2012, 12(4), 695-700.
[http://dx.doi.org/10.1016/j.meegid.2011.08.009] [PMID: 21871582]
Bustin, S.A.; Beaulieu, J-F.; Huggett, J.; Jaggi, R.; Kibenge, F.S.; Olsvik, P.A.; Penning, L.C.; Toegel, S. MIQE precis: Practical implementation of minimum standard guidelines for fluorescencebased quantitative real-time PCR experiments. In: BioMed Central, 2010.
Adami, A.G.; Gallo, J.F.; Pinhata, J.M.W.; Martins, M.C.; Giampaglia, C.M.S.; de Oliveira, R.S. Modified protocol for drug susceptibility testing of MGIT cultures of Mycobacterium tuberculosis by the MGIT 960. Diagn. Microbiol. Infect. Dis., 2017, 87(2), 108-111.
[http://dx.doi.org/10.1016/j.diagmicrobio.2016.10.023] [PMID: 27889251]
Nathanson, E.; Nunn, P.; Uplekar, M.; Floyd, K.; Jaramillo, E.; Lönnroth, K.; Weil, D.; Raviglione, M. MDR tuberculosis--critical steps for prevention and control. N. Engl. J. Med., 2010, 363(11), 1050-1058.
[http://dx.doi.org/10.1056/NEJMra0908076] [PMID: 20825317]
Organization, W. H. Multidrug and extensively drug-resistant TB (M/XDR-TB): 2010 global report on surveillance and response. Multidrug and extensively drug-resistant TB (M/XDR-TB): 2010 global report on surveillance and response, 2010.
Kolyva, A.S.; Karakousis, P.C. Old and new TB drugs: mechanisms of action and resistance.Understanding Tuberculosis-New Approaches to Fighting Against Drug Resistance; InTech, 2012.
Niehaus, A.J.; Mlisana, K.; Gandhi, N.R.; Mathema, B.; Brust, J.C. High prevalence of inhA promoter mutations among patients with drug-resistant tuberculosis in KwaZulu-Natal, South Africa. PLoS One, 2015, 10(9)e0135003
[http://dx.doi.org/10.1371/journal.pone.0135003] [PMID: 26332235]
Banerjee, A.; Dubnau, E.; Quemard, A.; Balasubramanian, V.; Um, K.S.; Wilson, T.; Collins, D.; de Lisle, G.; Jacobs, W.R. Jr inhA, a gene encoding a target for isoniazid and ethionamide in Mycobacterium tuberculosis. Science, 1994, 263(5144), 227-230.
[http://dx.doi.org/10.1126/science.8284673] [PMID: 8284673]
Bardou, F.; Raynaud, C.; Ramos, C.; Lanéelle, M.A.; Lanéelle, G. Mechanism of isoniazid uptake in Mycobacterium tuberculosis. Microbiology, 1998, 144(Pt 9), 2539-2544.
[http://dx.doi.org/10.1099/00221287-144-9-2539] [PMID: 9782502]
Basso, L.A.; Zheng, R.; Musser, J.M.; Jacobs, W.R., Jr; Blanchard, J.S. Mechanisms of isoniazid resistance in Mycobacterium tuberculosis: enzymatic characterization of enoyl reductase mutants identified in isoniazid-resistant clinical isolates. J. Infect. Dis., 1998, 178(3), 769-775.
[http://dx.doi.org/10.1086/515362] [PMID: 9728546]
Dessen, A.; Quémard, A.; Blanchard, J.S.; Jacobs, W.R., Jr; Sacchettini, J.C. Crystal structure and function of the isoniazid target of Mycobacterium tuberculosis. Science, 1995, 267(5204), 1638-1641.
[http://dx.doi.org/10.1126/science.7886450] [PMID: 7886450]
Heym, B.; Saint-Joanis, B.; Cole, S.T. The molecular basis of isoniazid resistance in Mycobacterium tuberculosis. Tuber. Lung Dis., 1999, 79(4), 267-271.
[http://dx.doi.org/10.1054/tuld.1998.0208] [PMID: 10692996]
Marrakchi, H.; Lanéelle, G.; Quémard, A.; Inh, A. InhA, a target of the antituberculous drug isoniazid, is involved in a mycobacterial fatty acid elongation system, FAS-II. Microbiology, 2000, 146(Pt 2), 289-296.
[http://dx.doi.org/10.1099/00221287-146-2-289] [PMID: 10708367]
Tudó, G.; Laing, K.; Mitchison, D.A.; Butcher, P.D.; Waddell, S.J. Examining the basis of isoniazid tolerance in nonreplicating Mycobacterium tuberculosis using transcriptional profiling. Future Med. Chem., 2010, 2(8), 1371-1383.
[http://dx.doi.org/10.4155/fmc.10.219] [PMID: 21426023]
Li, G.; Zhang, J.; Guo, Q.; Jiang, Y.; Wei, J.; Zhao, L.L.; Zhao, X.; Lu, J.; Wan, K. Efflux pump gene expression in multidrug-resistant Mycobacterium tuberculosis clinical isolates. PLoS One, 2015, 10(2)e0119013
[http://dx.doi.org/10.1371/journal.pone.0119013] [PMID: 25695504]
Ando, H.; Kitao, T.; Miyoshi-Akiyama, T.; Kato, S.; Mori, T.; Kirikae, T. Downregulation of katG expression is associated with isoniazid resistance in Mycobacterium tuberculosis. Mol. Microbiol., 2011, 79(6), 1615-1628.
[http://dx.doi.org/10.1111/j.1365-2958.2011.07547.x] [PMID: 21244531]
Sala, C.; Forti, F.; Magnoni, F.; Ghisotti, D. The katG mRNA of Mycobacterium tuberculosis and Mycobacterium smegmatis is processed at its 5′ end and is stabilized by both a polypurine sequence and translation initiation. BMC Mol. Biol., 2008, 9, 33.
[http://dx.doi.org/10.1186/1471-2199-9-33] [PMID: 18394163]
Peng, J.; Yu, X.; Cui, Z.; Xue, W.; Luo, Z.; Wen, Z.; Liu, M.; Jiang, D.; Zheng, H.; Wu, H.; Zhang, S.; Li, Y. Multi-Fluorescence Real-Time PCR Assay for Detection of RIF and INH Resistance of M. tuberculosis. Front. Microbiol., 2016, 7, 618.
[http://dx.doi.org/10.3389/fmicb.2016.00618] [PMID: 27199947]
Georghiou, S.B.; Seifert, M.; Catanzaro, D.; Garfein, R.S.; Valafar, F.; Crudu, V.; Rodrigues, C.; Victor, T.C.; Catanzaro, A.; Rodwell, T.C. Frequency and distribution of tuberculosis resistance-associated mutations between Mumbai, Moldova, and Eastern Cape. Antimicrob. Agents Chemother., 2016, 60(7), 3994-4004.
[http://dx.doi.org/10.1128/AAC.00222-16] [PMID: 27090176]
Bakonyte, D.; Baranauskaite, A.; Cicenaite, J.; Sosnovskaja, A.; Stakenas, P. Molecular characterization of isoniazid-resistant Mycobacterium tuberculosis clinical isolates in Lithuania. Antimicrob. Agents Chemother., 2003, 47(6), 2009-2011.
[http://dx.doi.org/10.1128/AAC.47.6.2009-2011.2003] [PMID: 12760887]
Mokrousov, I.; Narvskaya, O.; Otten, T.; Limeschenko, E.; Steklova, L.; Vyshnevskiy, B. High prevalence of KatG Ser315Thr substitution among isoniazid-resistant Mycobacterium tuberculosis clinical isolates from northwestern Russia, 1996 to 2001. Antimicrob. Agents Chemother., 2002, 46(5), 1417-1424.
[http://dx.doi.org/10.1128/AAC.46.5.1417-1424.2002] [PMID: 11959577]
Tracevska, T.; Jansone, I.; Broka, L.; Marga, O.; Baumanis, V. Mutations in the rpoB and katG genes leading to drug resistance in Mycobacterium tuberculosis in Latvia. J. Clin. Microbiol., 2002, 40(10), 3789-3792.
[http://dx.doi.org/10.1128/JCM.40.10.3789-3792.2002] [PMID: 12354882]
Silva, M.S.N.; Senna, S.G.; Ribeiro, M.O.; Valim, A.R.; Telles, M.A.; Kritski, A.; Morlock, G.P.; Cooksey, R.C.; Zaha, A.; Rossetti, M.L.R. Mutations in katG, inhA, and ahpC genes of Brazilian isoniazid-resistant isolates of Mycobacterium tuberculosis. J. Clin. Microbiol., 2003, 41(9), 4471-4474.
[http://dx.doi.org/10.1128/JCM.41.9.4471-4474.2003] [PMID: 12958298]
Cardoso, R.F.; Cooksey, R.C.; Morlock, G.P.; Barco, P.; Cecon, L.; Forestiero, F.; Leite, C.Q.; Sato, D.N. Shikama, Mde.L.; Mamizuka, E.M.; Hirata, R.D.; Hirata, M.H. Screening and characterization of mutations in isoniazid-resistant Mycobacterium tuberculosis isolates obtained in Brazil. Antimicrob. Agents Chemother., 2004, 48(9), 3373-3381.
[http://dx.doi.org/10.1128/AAC.48.9.3373-3381.2004] [PMID: 15328099]
Zhang, M.; Yue, J.; Yang, Y.P.; Zhang, H.M.; Lei, J.Q.; Jin, R.L.; Zhang, X.L.; Wang, H.H. Detection of mutations associated with isoniazid resistance in Mycobacterium tuberculosis isolates from China. J. Clin. Microbiol., 2005, 43(11), 5477-5482.
[http://dx.doi.org/10.1128/JCM.43.11.5477-5482.2005] [PMID: 16272473]
Ahmad, S.; Mokaddas, E. Contribution of AGC to ACC and other mutations at codon 315 of the katG gene in isoniazid-resistant Mycobacterium tuberculosis isolates from the Middle East. Int. J. Antimicrob. Agents, 2004, 23(5), 473-479.
[http://dx.doi.org/10.1016/j.ijantimicag.2003.10.004] [PMID: 15120726]
Lavender, C.; Globan, M.; Sievers, A.; Billman-Jacobe, H.; Fyfe, J. Molecular characterization of isoniazid-resistant Mycobacterium tuberculosis isolates collected in Australia. Antimicrob. Agents Chemother., 2005, 49(10), 4068-4074.
[http://dx.doi.org/10.1128/AAC.49.10.4068-4074.2005] [PMID: 16189082]
van Soolingen, D.; de Haas, P.E.; van Doorn, H.R.; Kuijper, E.; Rinder, H.; Borgdorff, M.W. Mutations at amino acid position 315 of the katG gene are associated with high-level resistance to isoniazid, other drug resistance, and successful transmission of Mycobacterium tuberculosis in the Netherlands. J. Infect. Dis., 2000, 182(6), 1788-1790.
[http://dx.doi.org/10.1086/317598] [PMID: 11069256]
García de Viedma, D.; del Sol Díaz Infantes, M.; Lasala, F.; Chaves, F.; Alcalá, L.; Bouza, E. New real-time PCR able to detect in a single tube multiple rifampin resistance mutations and high-level isoniazid resistance mutations in Mycobacterium tuberculosis. J. Clin. Microbiol., 2002, 40(3), 988-995.
[http://dx.doi.org/10.1128/JCM.40.3.988-995.2002] [PMID: 11880428]
Rindi, L.; Bianchi, L.; Tortoli, E.; Lari, N.; Bonanni, D.; Garzelli, C. Mutations responsible for Mycobacterium tuberculosis isoniazid resistance in Italy. Int. J. Tuberc. Lung Dis., 2005, 9(1), 94-97.
[PMID: 15675557]
Pym, A.S.; Domenech, P.; Honoré, N.; Song, J.; Deretic, V.; Cole, S.T. Regulation of catalase-peroxidase (KatG) expression, isoniazid sensitivity and virulence by furA of Mycobacterium tuberculosis. Mol. Microbiol., 2001, 40(4), 879-889.
[http://dx.doi.org/10.1046/j.1365-2958.2001.02427.x] [PMID: 11401695]
Zahrt, T.C.; Song, J.; Siple, J.; Deretic, V. Mycobacterial FurA is a negative regulator of catalase-peroxidase gene katG. Mol. Microbiol., 2001, 39(5), 1174-1185.
[http://dx.doi.org/10.1111/j.1365-2958.2001.02321.x] [PMID: 11251835]
Master, S.; Zahrt, T.C.; Song, J.; Deretic, V. Mapping of Mycobacterium tuberculosis katG promoters and their differential expression in infected macrophages. J. Bacteriol., 2001, 183(13), 4033-4039.
[http://dx.doi.org/10.1128/JB.183.13.4033-4039.2001] [PMID: 11395468]
Lee, J-H.; Ammerman, N.C.; Nolan, S.; Geiman, D.E.; Lun, S.; Guo, H.; Bishai, W.R. Isoniazid resistance without a loss of fitness in Mycobacterium tuberculosis. Nat. Commun., 2012, 3, 753.
[http://dx.doi.org/10.1038/ncomms1724] [PMID: 22434196]
Gagneux, S.; Burgos, M.V.; DeRiemer, K.; Encisco, A.; Muñoz, S.; Hopewell, P.C.; Small, P.M.; Pym, A.S. Impact of bacterial genetics on the transmission of isoniazid-resistant Mycobacterium tuberculosis. PLoS Pathog., 2006, 2(6)e61
[http://dx.doi.org/10.1371/journal.ppat.0020061] [PMID: 16789833]
Ramaswamy, S.V.; Reich, R.; Dou, S-J.; Jasperse, L.; Pan, X.; Wanger, A.; Quitugua, T.; Graviss, E.A. Single nucleotide polymorphisms in genes associated with isoniazid resistance in Mycobacterium tuberculosis. Antimicrob. Agents Chemother., 2003, 47(4), 1241-1250.
[http://dx.doi.org/10.1128/AAC.47.4.1241-1250.2003] [PMID: 12654653]
Heym, B.; Alzari, P.M.; Honoré, N.; Cole, S.T. Missense mutations in the catalase-peroxidase gene, katG, are associated with isoniazid resistance in Mycobacterium tuberculosis. Mol. Microbiol., 1995, 15(2), 235-245.
[http://dx.doi.org/10.1111/j.1365-2958.1995.tb02238.x] [PMID: 7746145]
Heym, B.; Cole, S.T. Isolation and characterization of isoniazid-resistant mutants of Mycobacterium smegmatis and M. aurum. Res. Microbiol., 1992, 143(7), 721-730.
[http://dx.doi.org/10.1016/0923-2508(92)90067-X] [PMID: 1488556]
Cade, C.E.; Dlouhy, A.C.; Medzihradszky, K.F.; Salas-Castillo, S.P.; Ghiladi, R.A. Isoniazid-resistance conferring mutations in Mycobacterium tuberculosis KatG: catalase, peroxidase, and INH-NADH adduct formation activities. Protein Sci., 2010, 19(3), 458-474.
[PMID: 20054829]
Ando, H.; Kondo, Y.; Suetake, T.; Toyota, E.; Kato, S.; Mori, T.; Kirikae, T. Identification of katG mutations associated with high-level isoniazid resistance in Mycobacterium tuberculosis. Antimicrob. Agents Chemother., 2010, 54(5), 1793-1799.
[http://dx.doi.org/10.1128/AAC.01691-09] [PMID: 20211896]
Zhang, Y.; Yew, W.W. Mechanisms of drug resistance in Mycobacterium tuberculosis. Int. J. Tuberc. Lung Dis., 2009, 13(11), 1320-1330. [State of the art series. Drug-resistant tuberculosis. Edited by CY. Chiang. Number 1 in the series
[PMID: 19861002]
Ng, V.H.; Cox, J.S.; Sousa, A.O.; MacMicking, J.D.; McKinney, J.D. Role of KatG catalase-peroxidase in mycobacterial pathogenesis: countering the phagocyte oxidative burst. Mol. Microbiol., 2004, 52(5), 1291-1302.
[http://dx.doi.org/10.1111/j.1365-2958.2004.04078.x] [PMID: 15165233]
Heym, B.; Stavropoulos, E.; Honoré, N.; Domenech, P.; Saint-Joanis, B.; Wilson, T.M.; Collins, D.M.; Colston, M.J.; Cole, S.T. Effects of overexpression of the alkyl hydroperoxide reductase AhpC on the virulence and isoniazid resistance of Mycobacterium tuberculosis. Infect. Immun., 1997, 65(4), 1395-1401.
[PMID: 9119479]
Pym, A.S.; Saint-Joanis, B.; Cole, S.T. Effect of katG mutations on the virulence of Mycobacterium tuberculosis and the implication for transmission in humans. Infect. Immun., 2002, 70(9), 4955-4960.
[http://dx.doi.org/10.1128/IAI.70.9.4955-4960.2002] [PMID: 12183541]
de Welzen, L.; Eldholm, V.; Maharaj, K.; Manson, A.L.; Earl, A.M.; Pym, A.S. Whole-transcriptome and-genome analysis of extensively drug-resistant Mycobacterium tuberculosis clinical isolates identifies downregulation of ethA as a mechanism of ethionamide resistance. Antimicrob. Agents Chemother., 2017, 61(12), e01461-e17.
[http://dx.doi.org/10.1128/AAC.01461-17] [PMID: 28993337]
Machado, D.; Coelho, T.S.; Perdigão, J.; Pereira, C.; Couto, I.; Portugal, I.; Maschmann, R.A.; Ramos, D.F.; von Groll, A.; Rossetti, M.L.R.; Silva, P.A.; Viveiros, M. Interplay between mutations and efflux in drug resistant clinical isolates of Mycobacterium tuberculosis. Front. Microbiol., 2017, 8, 711.
[http://dx.doi.org/10.3389/fmicb.2017.00711] [PMID: 28496433]
Machado, D.; Perdigão, J.; Ramos, J.; Couto, I.; Portugal, I.; Ritter, C.; Boettger, E.C.; Viveiros, M. High-level resistance to isoniazid and ethionamide in multidrug-resistant Mycobacterium tuberculosis of the Lisboa family is associated with inhA double mutations. J. Antimicrob. Chemother., 2013, 68(8), 1728-1732.
[http://dx.doi.org/10.1093/jac/dkt090] [PMID: 23539241]
Müller, B.; Streicher, E.M.; Hoek, K.G.; Tait, M.; Trollip, A.; Bosman, M.E.; Coetzee, G.J.; Chabula-Nxiweni, E.M.; Hoosain, E.; Gey van Pittius, N.C.; Victor, T.C.; van Helden, P.D.; Warren, R.M. inhA promoter mutations: a gateway to extensively drug-resistant tuberculosis in South Africa? Int. J. Tuberc. Lung Dis., 2011, 15(3), 344-351.
[PMID: 21333101]
Jagielski, T.; Bakuła, Z.; Roeske, K.; Kamiński, M.; Napiórkowska, A.; Augustynowicz-Kopeć, E.; Zwolska, Z.; Bielecki, J. Detection of mutations associated with isoniazid resistance in multidrug-resistant Mycobacterium tuberculosis clinical isolates. J. Antimicrob. Chemother., 2014, 69(9), 2369-2375.
[http://dx.doi.org/10.1093/jac/dku161] [PMID: 24855126]
Abate, D.; Tedla, Y.; Meressa, D.; Ameni, G. Isoniazid and rifampicin resistance mutations and their effect on second-line anti-tuberculosis treatment. Int. J. Tuberc. Lung Dis., 2014, 18(8), 946-951.
[http://dx.doi.org/10.5588/ijtld.13.0926] [PMID: 25199009]
Wade, M. M.; Zhang, Y. Mechanisms of drug resistance in Mycobacterium tuberculosis. Frontiers in bioscience: a journal and virtual library, 2004, 9, 975.
Herrera, L.; Valverde, A.; Saiz, P.; Sáez-Nieto, J.A.; Portero, J.L.; Jiménez, M.S. Molecular characterization of isoniazid-resistant Mycobacterium tuberculosis clinical strains isolated in the Philippines. Int. J. Antimicrob. Agents, 2004, 23(6), 572-576.
[http://dx.doi.org/10.1016/j.ijantimicag.2003.09.032] [PMID: 15194127]
Chihota, V.N.; Müller, B.; Mlambo, C.K.; Pillay, M.; Tait, M.; Streicher, E.M.; Marais, E.; van der Spuy, G.D.; Hanekom, M.; Coetzee, G. The population structure of multi-and extensively drug-resistant tuberculosis in South Africa. Journal of clinical microbiology, 2011, 05832-11. JCM.
Zhang, Y.; Heym, B.; Allen, B.; Young, D.; Cole, S. The catalase— peroxidase gene and isoniazid resistance of Mycobacterium tuberculosis. nature, 1992, (358), 591.
Vilchèze, C.; Jacobs, W.R. Resistance to isoniazid and ethionamide in Mycobacterium tuberculosis: genes, mutations, and causalities.Molecular Genetics of Mycobacteria, 2nd ed; American Society of Microbiology, 2014, pp. 431-453.
McMurry, L.M.; McDermott, P.F.; Levy, S.B. Genetic evidence that InhA of Mycobacterium smegmatis is a target for triclosan. Antimicrob. Agents Chemother., 1999, 43(3), 711-713.
[http://dx.doi.org/10.1128/AAC.43.3.711] [PMID: 10049298]
Larsen, M.H.; Vilchèze, C.; Kremer, L.; Besra, G.S.; Parsons, L.; Salfinger, M.; Heifets, L.; Hazbon, M.H.; Alland, D.; Sacchettini, J.C.; Jacobs, W.R. Jr Overexpression of inhA, but not kasA, confers resistance to isoniazid and ethionamide in Mycobacterium smegmatis, M. bovis BCG and M. tuberculosis. Mol. Microbiol., 2002, 46(2), 453-466.
[http://dx.doi.org/10.1046/j.1365-2958.2002.03162.x] [PMID: 12406221]
Brossier, F.; Veziris, N.; Truffot-Pernot, C.; Jarlier, V.; Sougakoff, W. Performance of the genotype MTBDR line probe assay for detection of resistance to rifampin and isoniazid in strains of Mycobacterium tuberculosis with low- and high-level resistance. J. Clin. Microbiol., 2006, 44(10), 3659-3664.
[http://dx.doi.org/10.1128/JCM.01054-06] [PMID: 17021094]
Morlock, G.P.; Metchock, B.; Sikes, D.; Crawford, J.T.; Cooksey, R.C. ethA, inhA, and katG loci of ethionamide-resistant clinical Mycobacterium tuberculosis isolates. Antimicrob. Agents Chemother., 2003, 47(12), 3799-3805.
[http://dx.doi.org/10.1128/AAC.47.12.3799-3805.2003] [PMID: 14638486]
Quémard, A.; Sacchettini, J.C.; Dessen, A.; Vilcheze, C.; Bittman, R.; Jacobs, W.R., Jr; Blanchard, J.S. Enzymatic characterization of the target for isoniazid in Mycobacterium tuberculosis. Biochemistry, 1995, 34(26), 8235-8241.
[http://dx.doi.org/10.1021/bi00026a004] [PMID: 7599116]
Kelley, C.L.; Rouse, D.A.; Morris, S.L. Analysis of ahpC gene mutations in isoniazid-resistant clinical isolates of Mycobacterium tuberculosis. Antimicrob. Agents Chemother., 1997, 41(9), 2057-2058.
[http://dx.doi.org/10.1128/AAC.41.9.2057] [PMID: 9303417]
Wilson, T.; de Lisle, G.W.; Marcinkeviciene, J.A.; Blanchard, J.S.; Collins, D.M. Antisense RNA to ahpC, an oxidative stress defence gene involved in isoniazid resistance, indicates that AhpC of Mycobacterium bovis has virulence properties. Microbiology, 1998, 144(Pt 10), 2687-2695.
[http://dx.doi.org/10.1099/00221287-144-10-2687] [PMID: 9802010]
Springer, B.; Master, S.; Sander, P.; Zahrt, T.; McFalone, M.; Song, J.; Papavinasasundaram, K.G.; Colston, M.J.; Boettger, E.; Deretic, V. Silencing of oxidative stress response in Mycobacterium tuberculosis: expression patterns of ahpC in virulent and avirulent strains and effect of ahpC inactivation. Infect. Immun., 2001, 69(10), 5967-5973.
[http://dx.doi.org/10.1128/IAI.69.10.5967-5973.2001] [PMID: 11553532]
Dhandayuthapani, S.; Zhang, Y.; Mudd, M.H.; Deretic, V. Oxidative stress response and its role in sensitivity to isoniazid in mycobacteria: characterization and inducibility of ahpC by peroxides in Mycobacterium smegmatis and lack of expression in M. aurum and M. tuberculosis. J. Bacteriol., 1996, 178(12), 3641-3649.
[http://dx.doi.org/10.1128/jb.178.12.3641-3649.1996] [PMID: 8655566]
Hazbón, M.H.; Brimacombe, M.; Bobadilla del Valle, M.; Cavatore, M.; Guerrero, M.I.; Varma-Basil, M.; Billman-Jacobe, H.; Lavender, C.; Fyfe, J.; García-García, L.; León, C.I.; Bose, M.; Chaves, F.; Murray, M.; Eisenach, K.D.; Sifuentes-Osornio, J.; Cave, M.D.; Ponce de León, A.; Alland, D. Population genetics study of isoniazid resistance mutations and evolution of multidrug-resistant Mycobacterium tuberculosis. Antimicrob. Agents Chemother., 2006, 50(8), 2640-2649.
[http://dx.doi.org/10.1128/AAC.00112-06] [PMID: 16870753]
Farr, S.B.; Kogoma, T. Oxidative stress responses in Escherichia coli and Salmonella typhimurium. Microbiol. Rev., 1991, 55(4), 561-585.
[PMID: 1779927]
Pagán-Ramos, E.; Master, S.S.; Pritchett, C.L.; Reimschuessel, R.; Trucksis, M.; Timmins, G.S.; Deretic, V. Molecular and physiological effects of mycobacterial oxyR inactivation. J. Bacteriol., 2006, 188(7), 2674-2680.
[http://dx.doi.org/10.1128/JB.188.7.2674-2680.2006] [PMID: 16547055]
Cardoso, R.F.; Cardoso, M.A.; Leite, C.Q.F.; Sato, D.N.; Mamizuka, E.M.; Hirata, R.D.C.; de Mello, F.F.; Hirata, M.H. Characterization of ndh gene of isoniazid resistant and susceptible Mycobacterium tuberculosis isolates from Brazil. Mem. Inst. Oswaldo Cruz, 2007, 102(1), 59-61.
[http://dx.doi.org/10.1590/S0074-02762007000100009] [PMID: 17294000]
Luo, T.; Zhao, M.; Li, X.; Xu, P.; Gui, X.; Pickerill, S.; DeRiemer, K.; Mei, J.; Gao, Q. Selection of mutations to detect multidrug-resistant Mycobacterium tuberculosis strains in Shanghai, China. Antimicrob. Agents Chemother., 2010, 54(3), 1075-1081.
[http://dx.doi.org/10.1128/AAC.00964-09] [PMID: 20008778]
Sreevatsan, S.; Pan, X.; Zhang, Y.; Deretic, V.; Musser, J.M. Analysis of the oxyR-ahpC region in isoniazid-resistant and -susceptible Mycobacterium tuberculosis complex organisms recovered from diseased humans and animals in diverse localities. Antimicrob. Agents Chemother., 1997, 41(3), 600-606.
[http://dx.doi.org/10.1128/AAC.41.3.600] [PMID: 9056000]
Ramaswamy, S.; Musser, J.M. Molecular genetic basis of antimicrobial agent resistance in Mycobacterium tuberculosis: 1998 update. Tuber. Lung Dis., 1998, 79(1), 3-29.
[http://dx.doi.org/10.1054/tuld.1998.0002] [PMID: 10645439]
Heep, M.; Brandstätter, B.; Rieger, U.; Lehn, N.; Richter, E.; Rüsch-Gerdes, S.; Niemann, S. Frequency of rpoB mutations inside and outside the cluster I region in rifampin-resistant clinical Mycobacterium tuberculosis isolates. J. Clin. Microbiol., 2001, 39(1), 107-110.
[http://dx.doi.org/10.1128/JCM.39.1.107-110.2001] [PMID: 11136757]
Musser, J.M. Antimicrobial agent resistance in mycobacteria: molecular genetic insights. Clin. Microbiol. Rev., 1995, 8(4), 496-514.
[http://dx.doi.org/10.1128/CMR.8.4.496] [PMID: 8665467]
Brandis, G.; Hughes, D. Genetic characterization of compensatory evolution in strains carrying rpoB Ser531Leu, the rifampicin resistance mutation most frequently found in clinical isolates. J. Antimicrob. Chemother., 2013, 68(11), 2493-2497.
[http://dx.doi.org/10.1093/jac/dkt224] [PMID: 23759506]
Qian, L.; Abe, C.; Lin, T-P.; Yu, M-C.; Cho, S-N.; Wang, S.; Douglas, J.T. rpoB genotypes of Mycobacterium tuberculosis Beijing family isolates from East Asian countries. J. Clin. Microbiol., 2002, 40(3), 1091-1094.
[http://dx.doi.org/10.1128/JCM.40.3.1091-1094.2002] [PMID: 11880449]
Chatterjee, A.; Saranath, D.; Bhatter, P.; Mistry, N. Global transcriptional profiling of longitudinal clinical isolates of Mycobacterium tuberculosis exhibiting rapid accumulation of drug resistance. PLoS One, 2013, 8(1)e54717
[http://dx.doi.org/10.1371/journal.pone.0054717] [PMID: 23355892]
Du Plessis, J. Deciphering the impact of rpoB mutations on the gene expression profile of Mycobacterium tuberculosis; Stellenbosch University: Stellenbosch, 2014.
Morris, R.P.; Nguyen, L.; Gatfield, J.; Visconti, K.; Nguyen, K.; Schnappinger, D.; Ehrt, S.; Liu, Y.; Heifets, L.; Pieters, J.; Schoolnik, G.; Thompson, C.J. Ancestral antibiotic resistance in Mycobacterium tuberculosis. Proc. Natl. Acad. Sci. USA, 2005, 102(34), 12200-12205.
[http://dx.doi.org/10.1073/pnas.0505446102] [PMID: 16103351]
Burian, J.; Yim, G.; Hsing, M.; Axerio-Cilies, P.; Cherkasov, A.; Spiegelman, G.B.; Thompson, C.J. The mycobacterial antibiotic resistance determinant WhiB7 acts as a transcriptional activator by binding the primary sigma factor SigA (RpoV). Nucleic Acids Res., 2013, 41(22), 10062-10076.
[http://dx.doi.org/10.1093/nar/gkt751] [PMID: 23990327]
Chikaonda, T.; Ketseoglou, I.; Nguluwe, N.; Krysiak, R.; Thengolose, I.; Nyakwawa, F.; Rosenberg, N.E.; Stanley, C.; Mpunga, J.; Hoffman, I.F.; Papathanasopoulos, M.A.; Hosseinipour, M.; Scott, L.; Stevens, W. Molecular characterisation of rifampicin-resistant Mycobacterium tuberculosis strains from Malawi. Afr. J. Lab. Med., 2017, 6(2), 463.
[http://dx.doi.org/10.4102/ajlm.v6i2.463] [PMID: 28879159]
Yue, J.; Shi, W.; Xie, J.; Li, Y.; Zeng, E.; Wang, H. Mutations in the rpoB gene of multidrug-resistant Mycobacterium tuberculosis isolates from China. J. Clin. Microbiol., 2003, 41(5), 2209-2212.
[http://dx.doi.org/10.1128/JCM.41.5.2209-2212.2003] [PMID: 12734282]
Khan, S.N.; Niemann, S.; Gulfraz, M.; Qayyum, M.; Siddiqi, S.; Mirza, Z.S.; Tahsin, S.; Ebrahimi-Rad, M.; Khanum, A. Molecular characterization of multidrug-resistant isolates of Mycobacterium tuberculosis from patients in Punjab, Pakistan. Pak. J. Zool., 2013, 45, 93-100.
Arnvig, K.B.; Comas, I.; Thomson, N.R.; Houghton, J.; Boshoff, H.I.; Croucher, N.J.; Rose, G.; Perkins, T.T.; Parkhill, J.; Dougan, G.; Young, D.B. Sequence-based analysis uncovers an abundance of non-coding RNA in the total transcriptome of Mycobacterium tuberculosis. PLoS Pathog., 2011, 7(11)e1002342
[http://dx.doi.org/10.1371/journal.ppat.1002342] [PMID: 22072964]
Wassarman, K.M.; Storz, G. 6S RNA regulates E. coli RNA polymerase activity. Cell, 2000, 101(6), 613-623.
[http://dx.doi.org/10.1016/S0092-8674(00)80873-9] [PMID: 10892648]
Trotochaud, A.E.; Wassarman, K.M. A highly conserved 6S RNA structure is required for regulation of transcription. Nat. Struct. Mol. Biol., 2005, 12(4), 313-319.
[http://dx.doi.org/10.1038/nsmb917] [PMID: 15793584]
Mariam, D.H.; Mengistu, Y.; Hoffner, S.E.; Andersson, D.I. Effect of rpoB mutations conferring rifampin resistance on fitness of Mycobacterium tuberculosis. Antimicrob. Agents Chemother., 2004, 48(4), 1289-1294.
[http://dx.doi.org/10.1128/AAC.48.4.1289-1294.2004] [PMID: 15047531]
Song, W.; Shi, Y.; Xiao, M.; Lu, H.; Qu, T.; Li, P.; Wu, G.; Tian, Y. In vitro bactericidal activity of recombinant human β-defensin-3 against pathogenic bacterial strains in human tooth root canal. Int. J. Antimicrob. Agents, 2009, 33(3), 237-243.
[http://dx.doi.org/10.1016/j.ijantimicag.2008.05.022] [PMID: 18775647]
Brandis, G.; Wrande, M.; Liljas, L.; Hughes, D. Fitness-compensatory mutations in rifampicin-resistant RNA polymerase. Mol. Microbiol., 2012, 85(1), 142-151.
[http://dx.doi.org/10.1111/j.1365-2958.2012.08099.x] [PMID: 22646234]
Poon, A.; Davis, B.H.; Chao, L. The coupon collector and the suppressor mutation: estimating the number of compensatory mutations by maximum likelihood. Genetics, 2005, 170(3), 1323-1332.
[http://dx.doi.org/10.1534/genetics.104.037259] [PMID: 15879511]
Rifat, D.; Campodónico, V.L.; Tao, J.; Miller, J.A.; Alp, A.; Yao, Y.; Karakousis, P.C. In vitro and in vivo fitness costs associated with Mycobacterium tuberculosis RpoB mutation H526D. Future Microbiol., 2017, 12, 753-765.
[http://dx.doi.org/10.2217/fmb-2017-0022] [PMID: 28343421]
Campbell, E.A.; Korzheva, N.; Mustaev, A.; Murakami, K.; Nair, S.; Goldfarb, A.; Darst, S.A. Structural mechanism for rifampicin inhibition of bacterial rna polymerase. Cell, 2001, 104(6), 901-912.
[http://dx.doi.org/10.1016/S0092-8674(01)00286-0] [PMID: 11290327]
Vassylyev, D. G.; Vassylyeva, M. N.; Zhang, J.; Palangat, M.; Artsimovitch, I.; Landick, R. Structural basis for substrate loading in bacterial RNA polymerase. nature, 2007, (448), 163.
Manganelli, R.; Dubnau, E.; Tyagi, S.; Kramer, F.R.; Smith, I. Differential expression of 10 sigma factor genes in Mycobacterium tuberculosis. Mol. Microbiol., 1999, 31(2), 715-724.
[http://dx.doi.org/10.1046/j.1365-2958.1999.01212.x] [PMID: 10027986]
Bisson, G.P.; Mehaffy, C.; Broeckling, C.; Prenni, J.; Rifat, D.; Lun, D.S.; Burgos, M.; Weissman, D.; Karakousis, P.C.; Dobos, K. Upregulation of the phthiocerol dimycocerosate biosynthetic pathway by rifampicin-resistant, rpoB-mutant Mycobacterium tuberculosis. Journal of bacteriology., 2012, 01013-12.
du Preez, I.; Loots, T. Altered fatty acid metabolism due to rifampicin-resistance conferring mutations in the rpoB Gene of Mycobacterium tuberculosis: mapping the potential of pharmaco-metabolomics for global health and personalized medicine. OMICS, 2012, 16(11), 596-603.
[http://dx.doi.org/10.1089/omi.2012.0028] [PMID: 22966781]
Lahiri, N.; Shah, R.R.; Layre, E.; Young, D.; Ford, C.; Murray, M.B.; Fortune, S.M.; Moody, D.B. Rifampin resistance mutations are associated with broad chemical remodeling of Mycobacterium tuberculosis. J. Biol. Chem., 2016, 291(27), 14248-14256.
[http://dx.doi.org/10.1074/jbc.M116.716704] [PMID: 27226566]
Clark, T.G.; Mallard, K.; Coll, F.; Preston, M.; Assefa, S.; Harris, D.; Ogwang, S.; Mumbowa, F.; Kirenga, B.; O’Sullivan, D.M.; Okwera, A.; Eisenach, K.D.; Joloba, M.; Bentley, S.D.; Ellner, J.J.; Parkhill, J.; Jones-López, E.C.; McNerney, R. Elucidating emergence and transmission of multidrug-resistant tuberculosis in treatment experienced patients by whole genome sequencing. PLoS One, 2013, 8(12)e83012
[http://dx.doi.org/10.1371/journal.pone.0083012] [PMID: 24349420]
Khanna, A.; Raj, V.S.; Tarai, B.; Sood, R.; Pareek, P.K.; Upadhyay, D.J.; Sharma, P.; Rattan, A.; Saini, K.S.; Singh, H. Emergence and molecular characterization of extensively drug-resistant Mycobacterium tuberculosis clinical isolates from the Delhi Region in India. Antimicrob. Agents Chemother., 2010, 54(11), 4789-4793.
[http://dx.doi.org/10.1128/AAC.00661-10] [PMID: 20713679]
Viveiros, M.; Martins, M.; Rodrigues, L.; Machado, D.; Couto, I.; Ainsa, J.; Amaral, L. Inhibitors of mycobacterial efflux pumps as potential boosters for anti-tubercular drugs. Expert Rev. Anti Infect. Ther., 2012, 10(9), 983-998.
[http://dx.doi.org/10.1586/eri.12.89] [PMID: 23106274]
Black, P.A.; Warren, R.M.; Louw, G.E.; van Helden, P.D.; Victor, T.C.; Kana, B.D. Energy metabolism and drug efflux in Mycobacterium tuberculosis. Antimicrobial agents and chemotherapy., 2014, 02293-13.
da Silva, P.E.A.; Machado, D.; Ramos, D.; Couto, I.; Von Groll, A.; Viveiros, M. Efflux pumps in mycobacteria: antimicrobial resistance, physiological functions, and role in pathogenicity.Efflux-Mediated Antimicrobial Resistance in Bacteria; Springer, 2016, pp. 527-559.
Li, G.; Zhang, J.; Guo, Q.; Wei, J.; Jiang, Y.; Zhao, X.; Zhao, L.L.; Liu, Z.; Lu, J.; Wan, K. Study of efflux pump gene expression in rifampicin-monoresistant Mycobacterium tuberculosis clinical isolates. J. Antibiot. (Tokyo), 2015, 68(7), 431-435.
[http://dx.doi.org/10.1038/ja.2015.9] [PMID: 25690361]
Garima, K.; Pathak, R.; Tandon, R.; Rathor, N.; Sinha, R.; Bose, M.; Varma-Basil, M. Differential expression of efflux pump genes of Mycobacterium tuberculosis in response to varied subinhibitory concentrations of antituberculosis agents. Tuberculosis (Edinb.), 2015, 95(2), 155-161.
[http://dx.doi.org/10.1016/j.tube.2015.01.005] [PMID: 25680943]
Machado, D.; Pires, D.; Perdigão, J.; Couto, I.; Portugal, I.; Martins, M.; Amaral, L.; Anes, E.; Viveiros, M. Ion channel blockers as antimicrobial agents, efflux inhibitors, and enhancers of macrophage killing activity against drug resistant Mycobacterium tuberculosis. PLoS One, 2016, 11(2)e0149326
[http://dx.doi.org/10.1371/journal.pone.0149326] [PMID: 26919135]
AlMatar, M.; Var, I.; Kayar, B.; Eker, E.; Kafkas, E.; Zarifikhosroshahi, M.; Köksal, F. Evaluation of Polyphenolic Profile and Antibacterial Activity of Pomegranate Juice in Combination with Rifampin (R) against MDR-TB Clinical Isolates. Curr. Pharm. Biotechnol., 2019, 20(4), 317-326.
[http://dx.doi.org/10.2174/1389201020666190308130343] [PMID: 30854955]
Gupta, A. K.; Katoch, V. M.; Chauhan, D. S.; Sharma, R.; Singh, M.; Venkatesan, K.; Sharma, V. D. Microarray analysis of efflux pump genes in multidrug-resistant Mycobacterium tuberculosis during stress induced by common anti-tuberculous drugs. Microbial drug resistance, 2010, (16), 21-28.
Fu, L.M. Exploring drug action on Mycobacterium tuberculosis using affymetrix oligonucleotide genechips. Tuberculosis (Edinb.), 2006, 86(2), 134-143.
[http://dx.doi.org/10.1016/j.tube.2005.07.004] [PMID: 16246625]
Betts, J.C.; McLaren, A.; Lennon, M.G.; Kelly, F.M.; Lukey, P.T.; Blakemore, S.J.; Duncan, K. Signature gene expression profiles discriminate between isoniazid-, thiolactomycin-, and triclosan-treated Mycobacterium tuberculosis. Antimicrob. Agents Chemother., 2003, 47(9), 2903-2913.
[http://dx.doi.org/10.1128/AAC.47.9.2903-2913.2003] [PMID: 12936993]
Gupta, A.K.; Reddy, V.P.; Lavania, M.; Chauhan, D.S.; Venkatesan, K.; Sharma, V.D.; Tyagi, A.K.; Katoch, V.M. jefA (Rv2459), a drug efflux gene in Mycobacterium tuberculosis confers resistance to isoniazid & ethambutol. Indian J. Med. Res., 2010, 132, 176-188.
[PMID: 20716818]
Cole, S.; Brosch, R.; Parkhill, J.; Garnier, T.; Churcher, C.; Harris, D.; Gordon, S.; Eiglmeier, K.; Gas, S.; Barry Iii, C. Deciphering the biology of Mycobacterium tuberculosis from the complete genome sequence. nature, 1998, (393), 537.
De Rossi, E.; Arrigo, P.; Bellinzoni, M.; Silva, P.A.; Martín, C.; Aínsa, J.A.; Guglierame, P.; Riccardi, G. The multidrug transporters belonging to major facilitator superfamily in Mycobacterium tuberculosis. Mol. Med., 2002, 8(11), 714-724.
[http://dx.doi.org/10.1007/BF03402035] [PMID: 12520088]
De Rossi, E.; Aínsa, J.A.; Riccardi, G. Role of mycobacterial efflux transporters in drug resistance: an unresolved question. FEMS Microbiol. Rev., 2006, 30(1), 36-52.
[http://dx.doi.org/10.1111/j.1574-6976.2005.00002.x] [PMID: 16438679]
Li, X-Z.; Zhang, L.; Nikaido, H. Efflux pump-mediated intrinsic drug resistance in Mycobacterium smegmatis. Antimicrob. Agents Chemother., 2004, 48(7), 2415-2423.
[http://dx.doi.org/10.1128/AAC.48.7.2415-2423.2004] [PMID: 15215089]
Narang, A.; Giri, A.; Gupta, S.; Garima, K.; Bose, M.; Varma-Basil, M. Contribution of putative efflux pump genes to isoniazid resistance in clinical isolates of Mycobacterium tuberculosis. Int. J. Mycobacteriol., 2017, 6(2), 177-183.
[http://dx.doi.org/10.4103/ijmy.ijmy_26_17] [PMID: 28559521]
Pang, Y.; Lu, J.; Wang, Y.; Song, Y.; Wang, S.; Zhao, Y. Study of the rifampin mono-resistance mechanism in Mycobacterium tuberculosis. Antimicrobial agents and chemotherapy, 2012, 01024-12.
Choudhuri, B.S.; Bhakta, S.; Barik, R.; Basu, J.; Kundu, M.; Chakrabarti, P. Overexpression and functional characterization of an ABC (ATP-binding cassette) transporter encoded by the genes drrA and drrB of Mycobacterium tuberculosis. Biochem. J., 2002, 367(Pt 1), 279-285.
[http://dx.doi.org/10.1042/bj20020615] [PMID: 12057006]
Zhang, J.; Li, G.; Zhao, X.; Wan, K.; Lü, J. A primary investigation on the isoniazid-induced alterations in efflux gene expression among the isoniazid resistant Mycobacterium tuberculosis clinical isolates. Zhonghua liu xing bing xue za zhi= Zhonghua liuxingbingxue zazhi, 2013, 34, 379-384.

open access plus

Rights & PermissionsPrintExport Cite as

Article Details

Year: 2020
Published on: 14 February, 2020
Page: [271 - 287]
Pages: 17
DOI: 10.2174/1871530319666191009153834

Article Metrics

PDF: 38