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Resistance to Isoniazid and Ethionamide in : Genes, Mutations, and Causalities

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  • Authors: Catherine Vilchèze1, William R. Jacobs JR.2
  • Editors: Graham F. Hatfull3, William R. Jacobs Jr.4
  • VIEW AFFILIATIONS HIDE AFFILIATIONS
    Affiliations: 1: Howard Hughes Medical Institute, Department of Microbiology and Immunology, Albert Einstein College of Medicine, Bronx, NY 10461; 2: Howard Hughes Medical Institute, Department of Microbiology and Immunology, Albert Einstein College of Medicine, Bronx, NY 10461; 3: University of Pittsburgh, Pittsburgh, PA; 4: Howard Hughes Medical Institute, Albert Einstein College of Medicine, Bronx, NY
    • Source: microbiolspec July 2014 vol. 2 no. 4 doi:10.1128/microbiolspec.MGM2-0014-2013
  • Received 23 April 2013 Accepted 05 August 2013 Published 04 July 2014
  • W. R. Jacobs, Jr., [email protected]
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  • Abstract:

    Isoniazid (INH) is the cornerstone of tuberculosis (TB) chemotherapy, used for both treatment and prophylaxis of TB. The antimycobacterial activity of INH was discovered in 1952, and almost as soon as its activity was published, the first INH-resistant strains were reported. INH and its structural analog and second-line anti-TB drug ethionamide (ETH) are pro-drugs. INH is activated by the catalase-peroxidase KatG, while ETH is activated by the monooxygenase EthA. The resulting active species reacts with NAD to form an INH-NAD or ETH-NAD adduct, which inhibits the enoyl ACP reductase InhA, leading to mycolic acid biosynthesis inhibition and mycobacterial cell death. The major mechanism of INH resistance is mutation in encoding the activator of INH. One specific KatG variant, S315T, is found in 94% of INH-resistant clinical isolates. The second mechanism of INH resistance is a mutation in the promoter region of (c-15t), which results in overexpression and leads to titration of the drug. Mutations in the open reading frame and promoter region are also the major mechanism of resistance to ETH, found more often in ETH-resistant clinical isolates than mutations in the activator of ETH. Other mechanisms of resistance to INH and ETH include expression changes of the drugs’ activators, redox alteration, drug inactivation, and efflux pump activation. In this article, we describe each known mechanism of resistance to INH and ETH and its importance in clinical isolates.

  • Citation: Vilchèze C, Jacobs JR. W. 2014. Resistance to Isoniazid and Ethionamide in : Genes, Mutations, and Causalities. Microbiol Spectrum 2(4):MGM2-0014-2013. doi:10.1128/microbiolspec.MGM2-0014-2013.

References

1. Behnisch R, Mietzsch F, Schmidt H. 1950. Chemical studies on thiosemicarbazones with particular reference to antituberculous activity. Am Rev Tuberc 61:1–7. [PubMed]
2. Domagk G. 1950. Investigations on the antituberculous activity of the thiosemicarbazones in vitro and in vivo. Am Rev Tuberc 61:8–19. [PubMed]
3. Schatz A, Waksman SA. 1944. Effect of streptomycin upon Mycobacterium tuberculosis and related organisms. Proc Soc Exp Biol Med 57:244–248. [CrossRef]
4. Lehmann J. 1946. para-Aminosalicylic acid in the treatment of tuberculosis. Lancet 247:15. [PubMed][CrossRef]
5. Bernstein JW, Lott A, Steinberg BA, Yale HL. 1952. Chemotherapy of experimental tuberculosis. Am Rev Tuberc 65:357–374. [PubMed]
6. Fox HH. 1952. The chemical approach to the control of tuberculosis. Science 116:129–134. [PubMed][CrossRef]
7. Medical Research Council Investigation. 1950. Treatment of pulmonary tuberculosis with streptomycin and para-amino-salicylic acid. Br MedJ 2:1073–1085. [PubMed][CrossRef]
8. Medical Research Council Investigation. 1952. The treatment of pulmonary tuberculosis with isoniazid. Br Med J 2:735–746. [CrossRef]
9. Crofton J, Mitchison DA. 1948. Streptomycin resistance in pulmonary tuberculosis. Br Med J 2:1009–1015. [PubMed][CrossRef]
10. Crofton J. 1959. Chemotherapy of pulmonary tuberculosis. Br Med J 1:1610–1614. [PubMed][CrossRef]
11. WHO. 2012. Global Tuberculosis Report 2012. Geneva, Switzerland.
12. Cegielski P, Nunn P, Kurbatova EV, Weyer K, Dalton TL, Wares DF, Iademarco MF, Castro KG, Raviglione M. 2012. Challenges and controversies in defining totally drug-resistant tuberculosis. Emerg Infect Dis 18:e2. [PubMed][CrossRef]
13. Domagk G, Offe HA, Siefken W. 1952. [Additional investigations in experimental chemotherapy of tuberculosis (neoteban)]. Dtsch Med Wochenschr 77:573–578. [PubMed][CrossRef]
14. Chorine V. 1945. Action of nicotinamide on bacilli of the species Mycobacterium. Compt Ren 220:150–151.
15. Barclay WR, Ebert RH, Kochweser D. 1953. Mode of action of isoniazid. Am Rev Tuberc 67:490–496. [PubMed]
16. Pope H. 1953. Antagonism of isoniazid by certain metabolites. Am Rev Tuberc 68:938–939. [PubMed]
17. Russe HP, Barclay WR. 1955. The effect of isoniazid on lipids of the tubercle bacillus. Am Rev Tuberc 72:713–717. [PubMed]
18. Ebina T, Motomiya M, Munakata K, Kobuya G. 1961. Effect of isoniazid on fatty acids in Mycobacterium. CR Seances Soc Biol Fil 155:1176–1178. [PubMed]
19. Gangadharam PRJ, Harold FM, Schaefer W. 1963. Selective inhibition of nucleic acid synthesis in Mycobacterium tuberculosis by isoniazid. Nature 198:712–714. [PubMed][CrossRef]
20. Winder FG, Brennan P. 1965. Effect of isoniazid on lipid metabolism in Mycobacterium tuberculosis. Biochem J 96:77P.
21. Bekierkunst A. 1966. Nicotinamide-adenine dinucleotide in tubercle bacilli exposed to isoniazid. Science 152:525–526. [PubMed][CrossRef]
22. Davis WE, Weber MM. 1977. Specificity of isoniazid on growth inhibition and competition for an oxidized nicotinamide adenine dinucleotide regulatory site on the electron transport pathway in Mycobacterium phlei. Antimicrob Agents Chemother 12:213–218. [PubMed][CrossRef]
23. Herman RP, Weber MM. 1980. Site of action of isoniazid on the electron transport chain and its relationship to nicotinamide adenine dinucleotide regulation in Mycobacterium phlei. Antimicrob Agents Chemother 17:450–454. [PubMed][CrossRef]
24. Takayama K, Wang L, David HL. 1972. Effect of isoniazid on the in vivo mycolic acid synthesis, cell growth, and viability of Mycobacterium tuberculosis. Antimicrob Agents Chemother 2:29–35. [PubMed][CrossRef]
25. Takayama K, Schnoes HK, Armstrong EL, Boyle RW. 1975. Site of inhibitory action of isoniazid in the synthesis of mycolic acids in Mycobacterium tuberculosis. J Lipid Res 16:308–317. [PubMed]
26. Davidson LA, Takayama K. 1979. Isoniazid inhibition of the synthesis of monounsaturated long-chain fatty acids in Mycobacterium tuberculosis H37Ra. Antimicrob Agents Chemother 16:104–105. [PubMed][CrossRef]
27. Johnsson K, Schultz PG. 1994. Mechanistic studies of the oxidation of isoniazid by the catalase peroxidase from Mycobacterium tuberculosis. J Am Chem Soc 116:7425–7426. [CrossRef]
28. Lei B, Wei CJ, Tu SC. 2000. Action mechanism of antitubercular isoniazid. Activation by Mycobacterium tuberculosis KatG, isolation, and characterization of inhA inhibitor. J Biol Chem 275:2520–2526. [PubMed][CrossRef]
29. Wilming M, Johnsson K. 1999. Spontaneous formation of the bioactive form of the tuberculosis drug isoniazid. Angew Chem Int Ed Engl 38:2588–2590. [PubMed][CrossRef]
30. Zhang Y, Heym B, Allen B, Young D, Cole S. 1992. The catalase-peroxidase gene and isoniazid resistance of Mycobacterium tuberculosis. Nature 358:591–593. [PubMed][CrossRef]
31. Rozwarski DA, Grant GA, Barton DH, Jacobs WR, Jr, Sacchettini JC. 1998. Modification of the NADH of the isoniazid target (InhA) from Mycobacterium tuberculosis. Science 279:98–102. [PubMed][CrossRef]
32. Dessen A, Quemard A, Blanchard JS, Jacobs WR, Jr, Sacchettini JC. 1995. Crystal structure and function of the isoniazid target of Mycobacterium tuberculosis. Science 267:1638–1641. [PubMed][CrossRef]
33. Quemard A, Sacchettini JC, Dessen A, Vilcheze C, Bittman R, Jacobs WR, Jr, Blanchard JS. 1995. Enzymatic characterization of the target for isoniazid in Mycobacterium tuberculosis. Biochemistry 34:8235–8241. [PubMed][CrossRef]
34. Marrakchi H, Laneelle G, Quemard A. 2000. InhA, a target of the antituberculous drug isoniazid, is involved in a mycobacterial fatty acid elongation system, FAS-II. Microbiology 146(Pt 2) :289–296. [PubMed]
35. Nguyen M, Quemard A, Broussy S, Bernadou J, Meunier B. 2002. Mn(III) pyrophosphate as an efficient tool for studying the mode of action of isoniazid on the InhA protein of Mycobacterium tuberculosis. Antimicrob Agents Chemother 46:2137–2144. [PubMed][CrossRef]
36. Rawat R, Whitty A, Tonge PJ. 2003. The isoniazid-NAD adduct is a slow, tight-binding inhibitor of InhA, the Mycobacterium tuberculosis enoyl reductase: adduct affinity and drug resistance. Proc Natl Acad Sci USA 100:13881–13886. [PubMed][CrossRef]
37. Vilcheze C, Morbidoni HR, Weisbrod TR, Iwamoto H, Kuo M, Sacchettini JC, Jacobs WR, Jr. 2000. Inactivation of the inhA-encoded fatty acid synthase II (FASII) enoyl-acyl carrier protein reductase induces accumulation of the FASI end products and cell lysis of Mycobacterium smegmatis. J Bacteriol 182:4059–4067. [PubMed][CrossRef]
38. Vilcheze C, Wang F, Arai M, Hazbon MH, Colangeli R, Kremer L, Weisbrod TR, Alland D, Sacchettini JC, Jacobs WR, Jr. 2006. Transfer of a point mutation in Mycobacterium tuberculosis inhA resolves the target of isoniazid. Nat Med 12:1027–1029. [PubMed][CrossRef]
39. Grumbach F, Rist N, Libermann D, Moyeux M, Cals S, Clavel S. 1956. Experimental antituberculous activity of certain isonicotinic thioamides substituted on the nucleus. CR Hebd Seances Acad Sci 242:2187–2189. (In French.) [PubMed]
40. Brouet G, Marche J, Rist N, Chevallier J, Lemeur G. 1959. Observations on the antituberculous effectiveness of alpha-ethyl-thioisonicotinamide in tuberculosis in humans. Am Rev Tuberc 79:6–18. [PubMed]
41. Petty TL, Mitchell RS. 1962. Successful treatment of advanced isonizid- and streptomycin-resistant pulmonary tuberculosis with ethionamide, pyrazinamide, and isoniazid. Am Rev Respir Dis 86:503–512. [PubMed]
42. Middlebrook G. 1952. Sterilization of tubercle bacilli by isonicotinic acid hydrazide and the incidence of variants resistant to the drug in vitro. Am Rev Tuberc 65:765–767. [PubMed]
43. Schaefer WB. 1954. The effect of isoniazid on growing and resting tubercle bacilli. Am Rev Tuberc 69:125–127. [PubMed]
44. Winder FG, Collins PB, Whelan D. 1971. Effects of ethionamide and isoxyl on mycolic acid synthesis in Mycobacterium tuberculosis BCG. J Gen Microbiol 66:379–380. [PubMed][CrossRef]
45. Baulard AR, Betts JC, Engohang-Ndong J, Quan S, McAdam RA, Brennan PJ, Locht C, Besra GS. 2000. Activation of the pro-drug ethionamide is regulated in mycobacteria. J Biol Chem 275:28326–28331. [PubMed]
46. DeBarber AE, Mdluli K, Bosman M, Bekker LG, Barry CE, 3rd. 2000. Ethionamide activation and sensitivity in multidrug-resistant Mycobacterium tuberculosis. Proc Natl Acad Sci USA 97:9677–9682. [PubMed][CrossRef]
47. Fraaije MW, Kamerbeek NM, Heidekamp AJ, Fortin R, Janssen DB. 2004. The prodrug activator EtaA from Mycobacterium tuberculosis is a Baeyer-Villiger monooxygenase. J Biol Chem 279:3354–3360. [PubMed][CrossRef]
48. Vannelli TA, Dykman A, Ortiz de Montellano PR. 2002. The antituberculosis drug ethionamide is activated by a flavoprotein monooxygenase. J Biol Chem 277:12824–12829. [PubMed][CrossRef]
49. Wang F, Langley R, Gulten G, Dover LG, Besra GS, Jacobs WR, Jr, Sacchettini JC. 2007. Mechanism of thioamide drug action against tuberculosis and leprosy. J Exp Med 204:73–78. [PubMed][CrossRef]
50. Dover LG, Alahari A, Gratraud P, Gomes JM, Bhowruth V, Reynolds RC, Besra GS, Kremer L. 2007. EthA, a common activator of thiocarbamide-containing drugs acting on different mycobacterial targets. Antimicrob Agents Chemother 51:1055–1063. [PubMed][CrossRef]
51. Hok TT. 1964. A comparative study of the susceptibility to ethionamide, thiosemicarbazone, and isoniazid of tubercle bacilli from patients never treated with ethionamide or thiosemicarbazone. Am Rev Respir Dis 90:468–469. [PubMed]
52. Stewart SM, Hall E, Riddell RW, Somner AR. 1962. Bacteriological aspects of the use of ethionamide, pyrazinamide and cycloserine in the treatment of chronic pulmonary tuberculosis. Tubercle 43:417–431. [PubMed][CrossRef]
53. Lefford MJ. 1966. The ethionamide sensitivity of British pre-treatment strains of Mycobacterium tuberculosis. Tubercle 47:198–206. [PubMed][CrossRef]
54. Snapper SB, Lugosi L, Jekkel A, Melton RE, Kieser T, Bloom BR, Jacobs WR, Jr. 1988. Lysogeny and transformation in mycobacteria: stable expression of foreign genes. Proc Natl Acad Sci USA 85:6987–6991. [PubMed][CrossRef]
55. Snapper SB, Melton RE, Mustafa S, Kieser T, Jacobs WR, Jr. 1990. Isolation and characterization of efficient plasmid transformation mutants of Mycobacterium smegmatis. Mol Microbiol 4:1911–1919. [PubMed][CrossRef]
56. Banerjee A, Dubnau E, Quemard A, Balasubramanian V, Um KS, Wilson T, Collins D, de Lisle G, Jacobs WR, Jr. 1994. inhA, a gene encoding a target for isoniazid and ethionamide in Mycobacterium tuberculosis. Science 263:227–230. [PubMed][CrossRef]
57. Takayama K, Wang L, Merkal RS. 1973. Scanning electron microscopy of the H37Ra strain of Mycobacterium tuberculosis exposed to isoniazid. Antimicrob Agents Chemother 4:62–65. [PubMed][CrossRef]
58. Dias MV, Vasconcelos IB, Prado AM, Fadel V, Basso LA, de Azevedo WF, Jr, Santos DS. 2007. Crystallographic studies on the binding of isonicotinyl-NAD adduct to wild-type and isoniazid resistant 2-trans-enoyl-ACP (CoA) reductase from Mycobacterium tuberculosis. J Struct Biol 159:369–380. [PubMed][CrossRef]
59. Brossier F, Veziris N, Truffot-Pernot C, Jarlier V, Sougakoff W. 2006. 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 44:3659–3664. [PubMed][CrossRef]
60. Muller B, Streicher EM, Hoek KG, Tait M, Trollip A, Bosman ME, Coetzee GJ, Chabula-Nxiweni EM, Hoosain E, Gey van Pittius NC, Victor TC, van Helden PD, Warren RM. 2011. inhA promoter mutations: a gateway to extensively drug-resistant tuberculosis in South Africa? Int J Tuberc Lung Dis 15:344–351. [PubMed]
61. Morlock GP, Metchock B, Sikes D, Crawford JT, Cooksey RC. 2003. ethA, inhA, and katG loci of ethionamide-resistant clinical Mycobacterium tuberculosis isolates. Antimicrob Agents Chemother 47:3799–3805. [PubMed][CrossRef]
62. Brossier F, Veziris N, Truffot-Pernot C, Jarlier V, Sougakoff W. 2011. Molecular investigation of resistance to the antituberculous drug ethionamide in multidrug-resistant clinical isolates of Mycobacterium tuberculosis. Antimicrob Agents Chemother 55:355–360. [PubMed][CrossRef]
63. Vadwai V, Ajbani K, Jose M, Vineeth VP, Nikam C, Deshmukh M, Shetty A, Soman R, Rodrigues C. 2012. Can inhA mutation predict ethionamide resistance? Int J Tuberc Lung Dis 17:129–130. [PubMed][CrossRef]
64. Miesel L, Weisbrod TR, Marcinkeviciene JA, Bittman R, Jacobs WR, Jr. 1998. NADH dehydrogenase defects confer isoniazid resistance and conditional lethality in Mycobacterium smegmatis. J Bacteriol 180:2459–2467. [PubMed]
65. Vilcheze C, Weisbrod TR, Chen B, Kremer L, Hazbon MH, Wang F, Alland D, Sacchettini JC, Jacobs WR, Jr. 2005. Altered NADH/NAD + ratio mediates coresistance to isoniazid and ethionamide in mycobacteria. Antimicrob Agents Chemother 49:708–720. [PubMed][CrossRef]
66. Hazbon MH, Brimacombe M, Bobadilla del Valle M, Cavatore M, Guerrero MI, Varma-Basil M, Billman-Jacobe H, Lavender C, Fyfe J, Garcia-Garcia L, Leon CI, Bose M, Chaves F, Murray M, Eisenach KD, Sifuentes-Osornio J, Cave MD, Ponce de Leon A, Alland D. 2006. Population genetics study of isoniazid resistance mutations and evolution of multidrug-resistant Mycobacterium tuberculosis. Antimicrob Agents Chemother 50:2640–2649. [PubMed][CrossRef]
67. Cardoso RF, Cardoso MA, Leite CQ, Sato DN, Mamizuka EM, Hirata RD, de Mello FF, Hirata MH. 2007. Characterization of ndh gene of isoniazid resistant and susceptible Mycobacterium tuberculosis isolates from Brazil. Mem Inst Oswaldo Cruz 102:59–61. [PubMed][CrossRef]
68. Lee AS, Teo AS, Wong SY. 2001. Novel mutations in ndh in isoniazid-resistant Mycobacterium tuberculosis isolates. Antimicrob Agents Chemother 45:2157–2159. [PubMed][CrossRef]
69. Lee AS, Lim IH, Tang LL, Telenti A, Wong SY. 1999. Contribution of kasA analysis to detection of isoniazid-resistant Mycobacterium tuberculosis in Singapore. Antimicrob Agents Chemother 43:2087–2089. [PubMed]
70. Vilcheze C, Av-Gay Y, Attarian R, Liu Z, Hazbon MH, Colangeli R, Chen B, Liu W, Alland D, Sacchettini JC, Jacobs WR, Jr. 2008. Mycothiol biosynthesis is essential for ethionamide susceptibility in Mycobacterium tuberculosis. Mol Microbiol 69:1316–1329. [PubMed][CrossRef]
71. Vilcheze C, Av-Gay Y, Barnes SW, Larsen MH, Walker JR, Glynne RJ, Jacobs WR, Jr. 2011. Coresistance to isoniazid and ethionamide maps to mycothiol biosynthetic genes in Mycobacterium bovis. Antimicrob Agents Chemother 55:4422–4423. [PubMed][CrossRef]
72. Newton GL, Buchmeier N, Fahey RC. 2008. Biosynthesis and functions of mycothiol, the unique protective thiol of Actinobacteria. Microbiol Mol Biol Rev 72:471–494. [PubMed][CrossRef]
73. Xu X, Vilcheze C, Av-Gay Y, Gomez-Velasco A, Jacobs WR, Jr. 2011. Precise null deletion mutations of the mycothiol synthesis genes reveal their role in isoniazid and ethionamide resistance in Mycobacterium smegmatis. Antimicrob Agents Chemother 55:3133–3139. [PubMed][CrossRef]
74. Rawat M, Johnson C, Cadiz V, Av-Gay Y. 2007. Comparative analysis of mutants in the mycothiol biosynthesis pathway in Mycobacterium smegmatis. Biochem Biophys Res Commun 363:71–76. [PubMed][CrossRef]
75. Projahn M, Koser CU, Homolka S, Summers DK, Archer JA, Niemann S. 2011. Polymorphisms in isoniazid and prothionamide resistance genes of the Mycobacterium tuberculosis complex. Antimicrob Agents Chemother 55:4408–4411. [PubMed][CrossRef]
76. Wang XD, Gu J, Wang T, Bi LJ, Zhang ZP, Cui ZQ, Wei HP, Deng JY, Zhang XE. 2011. Comparative analysis of mycobacterial NADH pyrophosphatase isoforms reveals a novel mechanism for isoniazid and ethionamide inactivation. Mol Microbiol 82:1375–1391. [PubMed][CrossRef]
77. Middlebrook G. 1954. Isoniazid resistance and catalase activity of tubercle bacilli. Am Rev Tuberc 69:471–472. [PubMed]
78. Middlebrook G, Cohn ML. 1953. Some observations on the pathogenicity of isoniazid-resistant variants of tubercle bacilli. Science 118:297–299. [PubMed][CrossRef]
79. Winder F. 1960. Catalase and peroxidase in mycobacteria. Possible relationship to the mode of action of isoniazid. Am Rev Respir Dis 81:68–78. [PubMed]
80. Zhang Y, Garbe T, Young D. 1993. Transformation with katG restores isoniazid-sensitivity in Mycobacterium tuberculosis isolates resistant to a range of drug concentrations. Mol Microbiol 8:521–524. [PubMed][CrossRef]
81. Mokrousov I, Narvskaya O, Otten T, Limeschenko E, Steklova L, Vyshnevskiy B. 2002. High prevalence of KatG Ser315Thr substitution among isoniazid-resistant Mycobacterium tuberculosis clinical isolates from northwestern Russia, 1996 to 2001. Antimicrob Agents Chemother 46:1417–1424. [PubMed][CrossRef]
82. Wengenack NL, Uhl JR, St Amand AL, Tomlinson AJ, Benson LM, Naylor S, Kline BC, Cockerill FR, 3rd, Rusnak F. 1997. Recombinant Mycobacterium tuberculosis KatG(S315T) is a competent catalase-peroxidase with reduced activity toward isoniazid. J Infect Dis 176:722–727. [PubMed][CrossRef]
83. Saint-Joanis B, Souchon H, Wilming M, Johnsson K, Alzari PM, Cole ST. 1999. Use of site-directed mutagenesis to probe the structure, function and isoniazid activation of the catalase/peroxidase, KatG, from Mycobacterium tuberculosis. Biochem J 338(Pt 3) :753–760. [PubMed][CrossRef]
84. Ramaswamy S, Musser JM. 1998. Molecular genetic basis of antimicrobial agent resistance in Mycobacterium tuberculosis: 1998 update. Tuber Lung Dis 79:3–29. [PubMed][CrossRef]
85. van Doorn HR, Kuijper EJ, van der Ende A, Welten AG, van Soolingen D, de Haas PE, Dankert J. 2001. The susceptibility of Mycobacterium tuberculosis to isoniazid and the Arg→Leu mutation at codon 463 of katG are not associated. J Clin Microbiol 39:1591–1594. [PubMed][CrossRef]
86. van Soolingen D, de Haas PE, van Doorn HR, Kuijper E, Rinder H, Borgdorff MW. 2000. 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 182:1788–1790. [PubMed][CrossRef]
87. Wei CJ, Lei B, Musser JM, Tu SC. 2003. Isoniazid activation defects in recombinant Mycobacterium tuberculosis catalase-peroxidase (KatG) mutants evident in InhA inhibitor production. Antimicrob Agents Chemother 47:670–675. [PubMed][CrossRef]
88. Ramaswamy SV, Reich R, Dou SJ, Jasperse L, Pan X, Wanger A, Quitugua T, Graviss EA. 2003. Single nucleotide polymorphisms in genes associated with isoniazid resistance in Mycobacterium tuberculosis. Antimicrob Agents Chemother 47:1241–1250. [PubMed][CrossRef]
89. Cohn ML, Oda U, Kovitz C, Middlebrook G. 1954. Studies on isoniazid and tubercle bacilli. I. The isolation of isoniazid-resistant mutants in vitro. Am Rev Tuberc 70:465–475. [PubMed]
90. Cohn ML, Kovitz C, Oda U, Middlebrook G. 1954. Studies on isoniazid and tubercle bacilli. II. The growth requirements, catalase activities, and pathogenic properties of isoniazid-resistant mutants. Am Rev Tuberc 70:641–664. [PubMed]
91. Pym AS, Saint-Joanis B, Cole ST. 2002. Effect of katG mutations on the virulence of Mycobacterium tuberculosis and the implication for transmission in humans. Infect Immun 70:4955–4960. [PubMed][CrossRef]
92. Gagneux S, Burgos MV, DeRiemer K, Encisco A, Munoz S, Hopewell PC, Small PM, Pym AS. 2006. Impact of bacterial genetics on the transmission of isoniazid-resistant Mycobacterium tuberculosis. PLoS Pathog 2:e61. [PubMed][CrossRef]
93. Escalante P, McKean-Cowdin R, Ramaswamy SV, Williams-Bouyer N, Teeter LD, Jones B, Graviss EA. 2013. Can mycobacterial katG genetic changes in isoniazid-resistant tuberculosis influence human disease features? Int J Tuberc Lung Dis 17:641–51. [PubMed][CrossRef]
94. Pym AS, Domenech P, Honore N, Song J, Deretic V, Cole ST. 2001. Regulation of catalase-peroxidase (KatG) expression, isoniazid sensitivity and virulence by furA of Mycobacterium tuberculosis. Mol Microbiol 40:879–889. [PubMed][CrossRef]
95. Zahrt TC, Song J, Siple J, Deretic V. 2001. Mycobacterial FurA is a negative regulator of catalase-peroxidase gene katG. Mol Microbiol 39:1174–1185. [PubMed][CrossRef]
96. Ando H, Kitao T, Miyoshi-Akiyama T, Kato S, Mori T, Kirikae T. 2011. Downregulation of katG expression is associated with isoniazid resistance in Mycobacterium tuberculosis. Mol Microbiol 79:1615–1628. [PubMed][CrossRef]
97. Lee JH, Ammerman NC, Nolan S, Geiman DE, Lun S, Guo H, Bishai WR. 2012. Isoniazid resistance without a loss of fitness in Mycobacterium tuberculosis. Nat Commun 3:753. [PubMed][CrossRef]
98. Rosner JL. 1993. Susceptibilities of oxyR regulon mutants of Escherichia coli and Salmonella typhimurium to isoniazid. Antimicrob Agents Chemother 37:2251–2253. [PubMed][CrossRef]
99. Sreevatsan S, Pan X, Zhang Y, Deretic V, Musser JM. 1997. 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 41:600–606. [PubMed]
100. Sherman DR, Mdluli K, Hickey MJ, Arain TM, Morris SL, Barry CE, 3rd, Stover CK. 1996. Compensatory ahpC gene expression in isoniazid-resistant Mycobacterium tuberculosis. Science 272:1641–1643. [PubMed][CrossRef]
101. Ng VH, Cox JS, Sousa AO, MacMicking JD, McKinney JD. 2004. Role of KatG catalase-peroxidase in mycobacterial pathogenesis: countering the phagocyte oxidative burst. Mol Microbiol 52:1291–1302. [PubMed][CrossRef]
102. Baker LV, Brown TJ, Maxwell O, Gibson AL, Fang Z, Yates MD, Drobniewski FA. 2005. Molecular analysis of isoniazid-resistant Mycobacterium tuberculosis isolates from England and Wales reveals the phylogenetic significance of the ahpC -46A polymorphism. Antimicrob Agents Chemother 49:1455–1464. [PubMed][CrossRef]
103. Upton AM, Mushtaq A, Victor TC, Sampson SL, Sandy J, Smith DM, van Helden PV, Sim E. 2001. Arylamine N-acetyltransferase of Mycobacterium tuberculosis is a polymorphic enzyme and a site of isoniazid metabolism. Mol Microbiol 42:309–317. [PubMed][CrossRef]
104. Payton M, Auty R, Delgoda R, Everett M, Sim E. 1999. Cloning and characterization of arylamine N-acetyltransferase genes from Mycobacterium smegmatis and Mycobacterium tuberculosis: increased expression results in isoniazid resistance. J Bacteriol 181:1343–1347. [PubMed]
105. Bhakta S, Besra GS, Upton AM, Parish T, Sholto-Douglas-Vernon C, Gibson KJ, Knutton S, Gordon S, DaSilva RP, Anderton MC, Sim E. 2004. Arylamine N-acetyltransferase is required for synthesis of mycolic acids and complex lipids in Mycobacterium bovis BCG and represents a novel drug target. J Exp Med 199:1191–1199. [PubMed][CrossRef]
106. Alland D, Kramnik I, Weisbrod TR, Otsubo L, Cerny R, Miller LP, Jacobs WR, Jr, Bloom BR. 1998. Identification of differentially expressed mRNA in prokaryotic organisms by customized amplification libraries (DECAL): the effect of isoniazid on gene expression in Mycobacterium tuberculosis. Proc Natl Acad Sci USA 95:13227–13232. [PubMed][CrossRef]
107. Cole ST, Brosch R, Parkhill J, Garnier T, Churcher C, Harris D, Gordon SV, Eiglmeier K, Gas S, Barry CE, 3rd, Tekaia F, Badcock K, Basham D, Brown D, Chillingworth T, Connor R, Davies R, Devlin K, Feltwell T, Gentles S, Hamlin N, Holroyd S, Hornsby T, Jagels K, Krogh A, McLean J, Moule S, Murphy L, Oliver K, Osborne J, Quail MA, Rajandream MA, Rogers J, Rutter S, Seeger K, Skelton J, Squares R, Squares S, Sulston JE, Taylor K, Whitehead S, Barrell BG. 1998. Deciphering the biology of Mycobacterium tuberculosis from the complete genome sequence. Nature 393:537–544. [PubMed][CrossRef]
108. Wilson M, DeRisi J, Kristensen HH, Imboden P, Rane S, Brown PO, Schoolnik GK. 1999. Exploring drug-induced alterations in gene expression in Mycobacterium tuberculosis by microarray hybridization. Proc Natl Acad Sci USA 96:12833–12838. [PubMed][CrossRef]
109. Mdluli K, Slayden RA, Zhu Y, Ramaswamy S, Pan X, Mead D, Crane DD, Musser JM, Barry CE, 3rd. 1998. Inhibition of a Mycobacterium tuberculosis beta-ketoacyl ACP synthase by isoniazid. Science 280:1607–1610. [PubMed][CrossRef]
110. Kremer L, Dover LG, Morbidoni HR, Vilcheze C, Maughan WN, Baulard A, Tu S, Honore N, Deretic V, Sacchettini JC, Locht C, Jacobs WRJ, Besra G. 2003. Inhibition of InhA activity, but not KasA activity, induces formation of a KasA-containing complex in mycobacteria. J Biol Chem 278:20547–20554. [PubMed][CrossRef]
111. Colangeli R, Helb D, Sridharan S, Sun J, Varma-Basil M, Hazbon MH, Harbacheuski R, Megjugorac NJ, Jacobs WR, Jr, Holzenburg A, Sacchettini JC, Alland D. 2005. The Mycobacterium tuberculosis iniA gene is essential for activity of an efflux pump that confers drug tolerance to both isoniazid and ethambutol. Mol Microbiol 55:1829–1840. [PubMed][CrossRef]
112. Alland D, Steyn AJ, Weisbrod T, Aldrich K, Jacobs WR, Jr. 2000. Characterization of the Mycobacterium tuberculosis iniBAC promoter, a promoter that responds to cell wall biosynthesis inhibition. J Bacteriol 182:1802–1811. [PubMed][CrossRef]
113. Chen P, Bishai WR. 1998. Novel selection for isoniazid (INH) resistance genes supports a role for NAD +-binding proteins in mycobacterial INH resistance. Infect Immun 66:5099–5106. [PubMed]
114. Ducasse-Cabanot S, Cohen-Gonsaud M, Marrakchi H, Nguyen M, Zerbib D, Bernadou J, Daffe M, Labesse G, Quemard A. 2004. In vitro inhibition of the Mycobacterium tuberculosis beta-ketoacyl-acyl carrier protein reductase MabA by isoniazid. Antimicrob Agents Chemother 48:242–249. [PubMed][CrossRef]
115. Argyrou A, Vetting MW, Aladegbami B, Blanchard JS. 2006. Mycobacterium tuberculosis dihydrofolate reductase is a target for isoniazid. Nat Struct Mol Biol 13:408–413. [PubMed][CrossRef]
116. Wang F, Jain P, Gulten G, Liu Z, Feng Y, Ganesula K, Motiwala AS, Ioerger TR, Alland D, Vilcheze C, Jacobs WR, Jr, Sacchettini JC. 2010. Mycobacterium tuberculosis dihydrofolate reductase is not a target relevant to the antitubercular activity of isoniazid. Antimicrob Agents Chemother 54:3776–3782. [PubMed][CrossRef]
117. Ho YM, Sun YJ, Wong SY, Lee AS. 2009. Contribution of dfrA and inhA mutations to the detection of isoniazid-resistant Mycobacterium tuberculosis isolates. Antimicrob Agents Chemother 53:4010–4012. [PubMed][CrossRef]
118. Argyrou A, Jin L, Siconilfi-Baez L, Angeletti RH, Blanchard JS. 2006. Proteome-wide profiling of isoniazid targets in Mycobacterium tuberculosis. Biochemistry 45:13947–13953. [PubMed][CrossRef]
119. McMurry L, Petrucci RE, Jr, Levy SB. 1980. Active efflux of tetracycline encoded by four genetically different tetracycline resistance determinants in Escherichia coli. Proc Natl Acad Sci USA 77:3974–3977. [PubMed][CrossRef]
120. Ainsa JA, Blokpoel MC, Otal I, Young DB, De Smet KA, Martin C. 1998. Molecular cloning and characterization of Tap, a putative multidrug efflux pump present in Mycobacterium fortuitum and Mycobacterium tuberculosis. J Bacteriol 180:5836–5843. [PubMed]
121. Silva PE, Bigi F, Santangelo MP, Romano MI, Martin C, Cataldi A, Ainsa JA. 2001. Characterization of P55, a multidrug efflux pump in Mycobacterium bovis and Mycobacterium tuberculosis. Antimicrob Agents Chemother 45:800–804. [PubMed][CrossRef]
122. Gupta AK, Katoch VM, Chauhan DS, Sharma R, Singh M, Venkatesan K, Sharma VD. 2010. Microarray analysis of efflux pump genes in multidrug-resistant Mycobacterium tuberculosis during stress induced by common anti-tuberculous drugs. Microb Drug Resist 16:21–28. [PubMed][CrossRef]
123. Wang K, Pei H, Huang B, Zhu X, Zhang J, Zhou B, Zhu L, Zhang Y, Zhou FF. 2013. The expression of ABC efflux pump, Rv1217c-Rv1218c, and its association with multidrug resistance of Mycobacterium tuberculosis in China. Curr Microbiol 66:222–226. [PubMed][CrossRef]
124. Balganesh M, Kuruppath S, Marcel N, Sharma S, Nair A, Sharma U. 2010. Rv1218c, an ABC transporter of Mycobacterium tuberculosis with implications in drug discovery. Antimicrob Agents Chemother 54:5167–5172. [PubMed][CrossRef]
125. Domenech P, Reed MB, Barry CE, 3rd. 2005. Contribution of the Mycobacterium tuberculosis MmpL protein family to virulence and drug resistance. Infect Immun 73:3492–3501. [PubMed][CrossRef]
126. Li XZ, Zhang L, Nikaido H. 2004. Efflux pump-mediated intrinsic drug resistance in Mycobacterium smegmatis. Antimicrob Agents Chemother 48:2415–2423. [PubMed][CrossRef]
127. Pasca MR, Guglierame P, De Rossi E, Zara F, Riccardi G. 2005. mmpL7 gene of Mycobacterium tuberculosis is responsible for isoniazid efflux in Mycobacterium smegmatis. Antimicrob Agents Chemother 49:4775–4777. [PubMed][CrossRef]
128. Hillemann D, Rusch-Gerdes S, Richter E. 2007. Evaluation of the GenoType MTBDRplus assay for rifampin and isoniazid susceptibility testing of Mycobacterium tuberculosis strains and clinical specimens. J Clin Microbiol 45:2635–2640. [PubMed][CrossRef]
129. Hartkoorn RC, Sala C, Neres J, Pojer F, Magnet S, Mukherjee R, Uplekar S, Boy-Rottger S, Altmann KH, Cole ST. 2012. Towards a new tuberculosis drug: pyridomycin: nature’s isoniazid. EMBO Mol Med 4:1032–1042. [PubMed][CrossRef]
130. Valvatne H, Syre H, Kross M, Stavrum R, Ti T, Phyu S, Grewal HM. 2009. Isoniazid and rifampicin resistance-associated mutations in Mycobacterium tuberculosis isolates from Yangon, Myanmar: implications for rapid molecular testing. J Antimicrob Chemother 64:694–701. [PubMed][CrossRef]
131. Caws M, Duy PM, Tho DQ, Lan NT, Hoa DV, Farrar J. 2006. Mutations prevalent among rifampin- and isoniazid-resistant Mycobacterium tuberculosis isolates from a hospital in Vietnam. J Clin Microbiol 44:2333–2337. [PubMed][CrossRef]
132. Rindi L, Bianchi L, Tortoli E, Lari N, Bonanni D, Garzelli C. 2005. Mutations responsible for Mycobacterium tuberculosis isoniazid resistance in Italy. Int J Tuberc Lung Dis 9:94–97. [PubMed]
133. Huang WL, Chen HY, Kuo YM, Jou R. 2009. Performance assessment of the GenoType MTBDRplus test and DNA sequencing in detection of multidrug-resistant Mycobacterium tuberculosis. J Clin Microbiol 47:2520–2524. [PubMed][CrossRef]
134. Fenner L, Egger M, Bodmer T, Altpeter E, Zwahlen M, Jaton K, Pfyffer GE, Borrell S, Dubuis O, Bruderer T, Siegrist HH, Furrer H, Calmy A, Fehr J, Stalder JM, Ninet B, Bottger EC, Gagneux S. 2012. Effect of mutation and genetic background on drug resistance in Mycobacterium tuberculosis. Antimicrob Agents Chemother 56:3047–3053. [PubMed][CrossRef]
135. Zhang M, Yue J, Yang YP, Zhang HM, Lei JQ, Jin RL, Zhang XL, Wang HH. 2005. Detection of mutations associated with isoniazid resistance in Mycobacterium tuberculosis isolates from China. J Clin Microbiol 43:5477–5482. [PubMed][CrossRef]
136. Luo T, Zhao M, Li X, Xu P, Gui X, Pickerill S, DeRiemer K, Mei J, Gao Q. 2010. Selection of mutations to detect multidrug-resistant Mycobacterium tuberculosis strains in Shanghai, China. Antimicrob Agents Chemother 54:1075–1081. [PubMed][CrossRef]
137. Doustdar F, Khosravi AD, Farnia P, Masjedi MR, Velayati AA. 2008. Molecular analysis of isoniazid resistance in different genotypes of Mycobacterium tuberculosis isolates from Iran. Microb Drug Resist 14:273–279. [PubMed][CrossRef]
138. Rahim Z, Nakajima C, Raqib R, Zaman K, Endtz HP, van der Zanden AG, Suzuki Y. 2012. Molecular mechanism of rifampicin and isoniazid resistance in Mycobacterium tuberculosis from Bangladesh. Tuberculosis (Edinb) 92:529–534. [PubMed][CrossRef]
139. Cardoso RF, Cooksey RC, Morlock GP, Barco P, Cecon L, Forestiero F, Leite CQ, Sato DN, Shikama Mde L, Mamizuka EM, Hirata RD, Hirata MH. 2004. Screening and characterization of mutations in isoniazid-resistant Mycobacterium tuberculosis isolates obtained in Brazil. Antimicrob Agents Chemother 48:3373–3381. [PubMed][CrossRef]
140. Kiepiela P, Bishop KS, Smith AN, Roux L, York DF. 2000. Genomic mutations in the katG, inhA and aphC genes are useful for the prediction of isoniazid resistance in Mycobacterium tuberculosis isolates from Kwazulu Natal, South Africa. Tuber Lung Dis 80:47–56. [PubMed][CrossRef]
141. Rouse DA, Li Z, Bai GH, Morris SL. 1995. Characterization of the katG and inhA genes of isoniazid-resistant clinical isolates of Mycobacterium tuberculosis. Antimicrob Agents Chemother 39:2472–2477. [PubMed][CrossRef]
142. Guo H, Seet Q, Denkin S, Parsons L, Zhang Y. 2006. Molecular characterization of isoniazid-resistant clinical isolates of Mycobacterium tuberculosis from the USA. J Med Microbiol 55:1527–1531. [PubMed][CrossRef]
143. Lavender C, Globan M, Sievers A, Billman-Jacobe H, Fyfe J. 2005. Molecular characterization of isoniazid-resistant Mycobacterium tuberculosis isolates collected in Australia. Antimicrob Agents Chemother 49:4068–4074. [PubMed][CrossRef]
144. Silva MS, Senna SG, Ribeiro MO, Valim AR, Telles MA, Kritski A, Morlock GP, Cooksey RC, Zaha A, Rossetti ML. 2003. Mutations in katG, inhA, and ahpC genes of Brazilian isoniazid-resistant isolates of Mycobacterium tuberculosis. J Clin Microbiol 41:4471–4474. [PubMed][CrossRef]
145. Poudel A, Nakajima C, Fukushima Y, Suzuki H, Pandey BD, Maharjan B, Suzuki Y. 2012. Molecular characterization of multidrug-resistant Mycobacterium tuberculosis isolated in Nepal. Antimicrob Agents Chemother 56:2831–2836. [PubMed][CrossRef]
146. Sekiguchi J, Miyoshi-Akiyama T, Augustynowicz-Kopec E, Zwolska Z, Kirikae F, Toyota E, Kobayashi I, Morita K, Kudo K, Kato S, Kuratsuji T, Mori T, Kirikae T. 2007. Detection of multidrug resistance in Mycobacterium tuberculosis. J Clin Microbiol 45:179–192. [PubMed][CrossRef]
147. N’Guessan KR, Dosso M, Ekaza E, Kouakou J, Jarlier V. 2008. Molecular characterisation of isoniazid-resistant Mycobacterium tuberculosis isolated from new cases in Lagunes region (Cote d’Ivoire). Int J Antimicrob Agents 31:498–500. [PubMed][CrossRef]
148. Lin HL, Kim H, Yun Y, Park CG, Kim B, Park Y, Kook Y. 2007. Mutations of katG and inhA in MDR M. tuberculosis.Tuberc Respir Dis 63:128–138. [CrossRef]
149. Basso LA, Zheng R, Musser JM, Jacobs WR, Jr, Blanchard JS. 1998. Mechanisms of isoniazid resistance in Mycobacterium tuberculosis: enzymatic characterization of enoyl reductase mutants identified in isoniazid-resistant clinical isolates. J Infect Dis 178:769–775. [PubMed][CrossRef]
150. Sholto-Douglas-Vernon C, Sandy J, Victor TC, Sim E, Helden PD. 2005. Mutational and expression analysis of tbnat and its response to isoniazid. J Med Microbiol 54:1189–1197. [PubMed][CrossRef]
151. Ristow M, Mohlig M, Rifai M, Schatz H, Feldmann K, Pfeiffer A. 1995. New isoniazid/ethionamide resistance gene mutation and screening for multidrug-resistant Mycobacterium tuberculosis strains. Lancet 346:502–503. [PubMed][CrossRef]
152. Yoon JH, Nam JS, Kim KJ, Choi Y, Lee H, Cho SN, Ro YT. 2012. Molecular characterization of drug-resistant and -susceptible Mycobacterium tuberculosis isolated from patients with tuberculosis in Korea. Diagn Microbiol Infect Dis 72:52–61. [PubMed][CrossRef]
153. Chan RC, Hui M, Chan EW, Au TK, Chin ML, Yip CK, AuYeang CK, Yeung CY, Kam KM, Yip PC, Cheng AF. 2007. Genetic and phenotypic characterization of drug-resistant Mycobacterium tuberculosis isolates in Hong Kong. J Antimicrob Chemother 59:866–873. [PubMed][CrossRef]
154. Leung KL, Yip CW, Yeung YL, Wong KL, Chan WY, Chan MY, Kam KM. 2010. Usefulness of resistant gene markers for predicting treatment outcome on second-line anti-tuberculosis drugs. J Appl Microbiol 109:2087–2094. [PubMed][CrossRef]
155. Boonaiam S, Chaiprasert A, Prammananan T, Leechawengwongs M. 2010. Genotypic analysis of genes associated with isoniazid and ethionamide resistance in MDR-TB isolates from Thailand. Clin Microbiol Infect 16:396–399. [PubMed][CrossRef]
156. Lee H, Cho SN, Bang HE, Lee JH, Bai GH, Kim SJ, Kim JD. 2000. Exclusive mutations related to isoniazid and ethionamide resistance among Mycobacterium tuberculosis isolates from Korea. Int J Tuberc Lung Dis 4:441–447. [PubMed]
157. Marttila HJ, Soini H, Huovinen P, Viljanen MK. 1996. katG mutations in isoniazid-resistant Mycobacterium tuberculosis isolates recovered from Finnish patients. Antimicrob Agents Chemother 40:2187–2189. [PubMed]
158. Khanna A, Raj VS, Tarai B, Sood R, Pareek PK, Upadhyay DJ, Sharma P, Rattan A, Saini KS, Singh H. 2010. Emergence and molecular characterization of extensively drug-resistant Mycobacterium tuberculosis clinical isolates from the Delhi Region in India. Antimicrob Agents Chemother 54:4789–4793. [PubMed][CrossRef]
159. Ramaswamy SV, Dou SJ, Rendon A, Yang Z, Cave MD, Graviss EA. 2004. Genotypic analysis of multidrug-resistant Mycobacterium tuberculosis isolates from Monterrey, Mexico. J Med Microbiol 53:107–113. [PubMed][CrossRef]
160. Siddiqi N, Shamim M, Hussain S, Choudhary RK, Ahmed N, Prachee, Banerjee S, Savithri GR, Alam M, Pathak N, Amin A, Hanief M, Katoch VM, Sharma SK, Hasnain SE. 2002. Molecular characterization of multidrug-resistant isolates of Mycobacterium tuberculosis from patients in North India. Antimicrob Agents Chemother 46:443–450. [PubMed][CrossRef]
161. Torres MJ, Criado A, Gonzalez N, Palomares JC, Aznar J. 2002. Rifampin and isoniazid resistance associated mutations in Mycobacterium tuberculosis clinical isolates in Seville, Spain. Int J Tuberc Lung Dis 6:160–163. [PubMed]
162. Pretorius GS, van Helden PD, Sirgel F, Eisenach KD, Victor TC. 1995. Mutations in katG gene sequences in isoniazid-resistant clinical isolates of Mycobacterium tuberculosis are rare. Antimicrob Agents Chemother 39:2276–2281. [PubMed][CrossRef]
163. Cockerill FR, 3rd, Uhl JR, Temesgen Z, Zhang Y, Stockman L, Roberts GD, Williams DL, Kline BC. 1995. Rapid identification of a point mutation of the Mycobacterium tuberculosis catalase-peroxidase ( katG) gene associated with isoniazid resistance. J Infect Dis 171:240–245. [PubMed][CrossRef]
164. Ghiladi RA, Medzihradszky KF, Rusnak FM, Ortiz de Montellano PR. 2005. Correlation between isoniazid resistance and superoxide reactivity in Mycobacterium tuberculosis KatG. J Am Chem Soc 127:13428–13442. [PubMed][CrossRef]
165. Bolotin S, Alexander DC, Chedore P, Drews SJ, Jamieson F. 2009. Molecular characterization of drug-resistant Mycobacterium tuberculosis isolates from Ontario, Canada. J Antimicrob Chemother 64:263–266. [PubMed][CrossRef]
166. Mo L, Zhang W, Wang J, Weng XH, Chen S, Shao LY, Pang MY, Chen ZW. 2004. Three-dimensional model and molecular mechanism of Mycobacterium tuberculosis catalase-peroxidase (KatG) and isoniazid-resistant KatG mutants. Microb Drug Resist 10:269–279. [PubMed][CrossRef]
167. Ando H, Kondo Y, Suetake T, Toyota E, Kato S, Mori T, Kirikae T. 2010. Identification of katG mutations associated with high-level isoniazid resistance in Mycobacterium tuberculosis. Antimicrob Agents Chemother 54:1793–1799. [PubMed][CrossRef]
168. Jnawali HN, Hwang SC, Park YK, Kim H, Lee YS, Chung GT, Choe KH, Ryoo S. 2013. Characterization of mutations in multi- and extensive drug resistance among strains of Mycobacterium tuberculosis clinical isolates in Republic of Korea. Diagn Microbiol Infect Dis 76:187–196. [PubMed][CrossRef]
169. Doustdar F, Khosravi AD, Farnia P, Masjedi MR, Velayati AA. 2008. Molecular analysis of isoniazid resistance in different genotypes of Mycobacterium tuberculosis isolates from Iran. Microb Drug Resist 14:273–279. [PubMed][CrossRef]
170. Rouse DA, DeVito JA, Li Z, Byer H, Morris SL. 1996. Site-directed mutagenesis of the katG gene of Mycobacterium tuberculosis: effects on catalase-peroxidase activities and isoniazid resistance. Mol Microbiol 22:583–592. [PubMed][CrossRef]
171. Heym B, Alzari PM, Honore N, Cole ST. 1995. Missense mutations in the catalase-peroxidase gene, katG, are associated with isoniazid resistance in Mycobacterium tuberculosis. Mol Microbiol 15:235–245. [PubMed][CrossRef]
172. Yuan X, Zhang T, Kawakami K, Zhu J, Li H, Lei J, Tu S. 2012. Molecular characterization of multidrug- and extensively drug-resistant Mycobacterium tuberculosis strains in Jiangxi, China. J Clin Microbiol 50:2404–2413. [PubMed][CrossRef]
173. Ramirez MV, Cowart KC, Campbell PJ, Morlock GP, Sikes D, Winchell JM, Posey JE. 2010. Rapid detection of multidrug-resistant Mycobacterium tuberculosis by use of real-time PCR and high-resolution melt analysis. J Clin Microbiol 48:4003–4009. [PubMed][CrossRef]
174. Fang Z, Doig C, Rayner A, Kenna DT, Watt B, Forbes KJ. 1999. Molecular evidence for heterogeneity of the multiple-drug-resistant Mycobacterium tuberculosis population in Scotland (1990 to 1997). J Clin Microbiol 37:998–1003. [PubMed]
175. Abe C, Kobayashi I, Mitarai S, Wada M, Kawabe Y, Takashima T, Suzuki K, Sng LH, Wang S, Htay HH, Ogata H. 2008. Biological and molecular characteristics of Mycobacterium tuberculosis clinical isolates with low-level resistance to isoniazid in Japan. J Clin Microbiol 46:2263–2268. [PubMed][CrossRef]
176. Khadka DK, Eampokalap B, Panitchakorn J, Ramasoota P, Khusmith S. 2007. Multiple mutations in katG and inhA identified in Thai isoniazid-resistant Mycobacterium tuberculosis isolates. Southeast Asian J Trop Med Public Health 38:376–382. [PubMed]
177. Kim SY, Park YJ, Kim WI, Lee SH, Ludgerus Chang C, Kang SJ, Kang CS. 2003. Molecular analysis of isoniazid resistance in Mycobacterium tuberculosis isolates recovered from South Korea. Diagn Microbiol Infect Dis 47:497–502. [CrossRef]
178. Minh NN, Van Bac N, Son NT, Lien VT, Ha CH, Cuong NH, Mai CT, Le TH. 2012. Molecular characteristics of rifampin- and isoniazid-resistant Mycobacterium tuberculosis strains isolated in Vietnam. J Clin Microbiol 50:598–601. [PubMed][CrossRef]
179. Zakerbostanabad S, Titov LP, Bahrmand AR. 2008. Frequency and molecular characterization of isoniazid resistance in katG region of MDR isolates from tuberculosis patients in southern endemic border of Iran. Infect Genet Evol 8:15–19. [PubMed][CrossRef]
180. Zenteno-Cuevas R, Zenteno JC, Cuellar A, Cuevas B, Sampieri CL, Riviera JE, Parissi A. 2009. Mutations in rpoB and katG genes in Mycobacterium isolates from the Southeast of Mexico. Mem Inst Oswaldo Cruz 104:468–472. [PubMed][CrossRef]
181. Soudani A, Hadjfredj S, Zribi M, Messaadi F, Messaoud T, Masmoudi A, Fendri C. 2011. Genotypic and phenotypic characteristics of Tunisian isoniazid-resistant Mycobacterium tuberculosis strains. J Microbiol 49:413–417. [PubMed][CrossRef]
182. Haas WH, Schilke K, Brand J, Amthor B, Weyer K, Fourie PB, Bretzel G, Sticht-Groh V, Bremer HJ. 1997. Molecular analysis of katG gene mutations in strains of Mycobacterium tuberculosis complex from Africa. Antimicrob Agents Chemother 41:1601–1603. [PubMed]
183. Musser JM, Kapur V, Williams DL, Kreiswirth BN, van Soolingen D, van Embden JD. 1996. Characterization of the catalase-peroxidase gene ( katG) and inhA locus in isoniazid-resistant and -susceptible strains of Mycobacterium tuberculosis by automated DNA sequencing: restricted array of mutations associated with drug resistance. J Infect Dis 173:196–202. [PubMed][CrossRef]
184. Lipin MY, Stepanshina VN, Shemyakin IG, Shinnick TM. 2007. Association of specific mutations in katG, rpoB, rpsL and rrs genes with spoligotypes of multidrug-resistant Mycobacterium tuberculosis isolates in Russia. Clin Microbiol Infect 13:620–626. [PubMed][CrossRef]
185. Waksman SA. 1964. The Conquest of Tuberculosis. University of California Press, Berkeley.
186. Winder FG, Collins PB. 1970. Inhibition by isoniazid of synthesis of mycolic acids in Mycobacterium tuberculosis. J Gen Microbiol 63:41–48. [PubMed][CrossRef]
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/content/journal/microbiolspec/10.1128/microbiolspec.MGM2-0014-2013
2014-07-04
2021-02-28

Abstract:

Isoniazid (INH) is the cornerstone of tuberculosis (TB) chemotherapy, used for both treatment and prophylaxis of TB. The antimycobacterial activity of INH was discovered in 1952, and almost as soon as its activity was published, the first INH-resistant strains were reported. INH and its structural analog and second-line anti-TB drug ethionamide (ETH) are pro-drugs. INH is activated by the catalase-peroxidase KatG, while ETH is activated by the monooxygenase EthA. The resulting active species reacts with NAD to form an INH-NAD or ETH-NAD adduct, which inhibits the enoyl ACP reductase InhA, leading to mycolic acid biosynthesis inhibition and mycobacterial cell death. The major mechanism of INH resistance is mutation in encoding the activator of INH. One specific KatG variant, S315T, is found in 94% of INH-resistant clinical isolates. The second mechanism of INH resistance is a mutation in the promoter region of (c-15t), which results in overexpression and leads to titration of the drug. Mutations in the open reading frame and promoter region are also the major mechanism of resistance to ETH, found more often in ETH-resistant clinical isolates than mutations in the activator of ETH. Other mechanisms of resistance to INH and ETH include expression changes of the drugs’ activators, redox alteration, drug inactivation, and efflux pump activation. In this article, we describe each known mechanism of resistance to INH and ETH and its importance in clinical isolates.

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Resistance to Isoniazid and Ethionamide in : Genes, Mutations, and Causalities
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Citation: Vilchèze C, Jacobs JR. W. 2014. Resistance to isoniazid and ethionamide in : genes, mutations, and causalities. microbiolspec 2(4): doi:10.1128/microbiolspec.MGM2-0014-2013
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FIGURE 1
Early synthetic antituberculosis drugs.
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FIGURE 1

Early synthetic antituberculosis drugs.

Source: microbiolspec July 2014 vol. 2 no. 4 doi:10.1128/microbiolspec.MGM2-0014-2013
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FIGURE 2
Mechanism of action of INH and ETH. INH and ETH are activated by the catalase peroxidase KatG and monooxygenase EthA, respectively, to form a reactive species that binds to NAD. The resulting adducts, INH-NAD or ETH-NAD, inhibit the enoyl-ACP reductase InhA of the FASII system, resulting in mycolic acid biosynthesis inhibition.
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FIGURE 2

Mechanism of action of INH and ETH. INH and ETH are activated by the catalase peroxidase KatG and monooxygenase EthA, respectively, to form a reactive species that binds to NAD. The resulting adducts, INH-NAD or ETH-NAD, inhibit the enoyl-ACP reductase InhA of the FASII system, resulting in mycolic acid biosynthesis inhibition.

Source: microbiolspec July 2014 vol. 2 no. 4 doi:10.1128/microbiolspec.MGM2-0014-2013
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FIGURE 3
Relationship among the genes and proteins involved in the resistance to INH and ETH in . Connections in red indicate a negative relationship (degradation of an active molecule, negative regulator of an enzyme) that would lead to resistance to INH and/or ETH; in green are positive actions that would increase a strain fitness or susceptibility to the drugs. The dashed line points to an interaction that does not result directly in INH resistance or susceptibility.
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FIGURE 3

Relationship among the genes and proteins involved in the resistance to INH and ETH in . Connections in red indicate a negative relationship (degradation of an active molecule, negative regulator of an enzyme) that would lead to resistance to INH and/or ETH; in green are positive actions that would increase a strain fitness or susceptibility to the drugs. The dashed line points to an interaction that does not result directly in INH resistance or susceptibility.

Source: microbiolspec July 2014 vol. 2 no. 4 doi:10.1128/microbiolspec.MGM2-0014-2013
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Resistance to Isoniazid and Ethionamide in : Genes, Mutations, and Causalities
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Citation: Vilchèze C, Jacobs JR. W. 2014. Resistance to isoniazid and ethionamide in : genes, mutations, and causalities. microbiolspec 2(4): doi:10.1128/microbiolspec.MGM2-0014-2013
/content/microbiolspec/10.1128/microbiolspec.MGM2-0014-2013.T1
TABLE 1
Identified mutations in genes other than in INH-resistant strains
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TABLE 1

Identified mutations in genes other than in INH-resistant strains

Source: microbiolspec July 2014 vol. 2 no. 4 doi:10.1128/microbiolspec.MGM2-0014-2013
/content/microbiolspec/10.1128/microbiolspec.MGM2-0014-2013.T2
TABLE 2
Identified mutations in ETH-resistant strains
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TABLE 2

Identified mutations in ETH-resistant strains

Source: microbiolspec July 2014 vol. 2 no. 4 doi:10.1128/microbiolspec.MGM2-0014-2013
/content/microbiolspec/10.1128/microbiolspec.MGM2-0014-2013.T3
TABLE 3
Identified mutations in INH-resistant strains
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TABLE 3

Identified mutations in INH-resistant strains

Source: microbiolspec July 2014 vol. 2 no. 4 doi:10.1128/microbiolspec.MGM2-0014-2013
/content/microbiolspec/10.1128/microbiolspec.MGM2-0014-2013.T4
TABLE 4
Biochemical activity of KatG variants ( 87 , 146 , 167 )
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TABLE 4

Biochemical activity of KatG variants ( 87 , 146 , 167 )

Source: microbiolspec July 2014 vol. 2 no. 4 doi:10.1128/microbiolspec.MGM2-0014-2013

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