Overexpression of inhA, but not kasA, confers resistance to isoniazid and ethionamide in mycobacterium smegmatis, M. bovis BCG and M. tuberculosis

Molecular Microbiology

Volumn 46, Issue 2, 2002, Pages 453-466

  Larsen, Michelle H ^a   Vilchèze, Catherine ^a   Kremer, Laurent ^b   Besra, Gurdyal S ^c   Parsons, Linda ^d   Salfinger, Max ^d   Heifets, Leonid ^e   Hazbon, Manzour H ^f   Alland, David ^f   Sacchettini, James C ^g   Jacobs Jr , William R ^a  

^a ALBERT EINSTEIN COLLEGE OF MEDICINE   (United States)

^b INSTITUT PASTEUR DE LILLE   (France)

^c UNIVERSITY OF BIRMINGHAM   (United Kingdom)

^d WADSWORTH CENTER   (United States)

^e NATIONAL JEWISH MEDICAL AND RESEARCH CENTER   (United States)

^f MONTEFIORE MEDICAL CENTER   (United States)

^g TEXAS A AND M UNIVERSITY   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

BACTERIAL PROTEIN; ETHIONAMIDE; ISONIAZID; MESSENGER RNA; PROTEIN INHA; PROTEIN KASA; THIOLACTOMYCIN; UNCLASSIFIED DRUG;

ANTIBIOTIC RESISTANCE; ANTIBIOTIC SENSITIVITY; ARTICLE; BACTERIAL GROWTH; BACTERIAL STRAIN; CONTROLLED STUDY; GENE EXPRESSION; GENE INDUCTION; MINIMUM INHIBITORY CONCENTRATION; MYCOBACTERIUM BOVIS; MYCOBACTERIUM SMEGMATIS; MYCOBACTERIUM TUBERCULOSIS; NONHUMAN; PLASMID; PRIORITY JOURNAL; REVERSE TRANSCRIPTION POLYMERASE CHAIN REACTION;

3-OXOACYL-(ACYL-CARRIER-PROTEIN) SYNTHASE; ANTITUBERCULAR AGENTS; BACTERIAL PROTEINS; DRUG RESISTANCE, BACTERIAL; ETHIONAMIDE; HUMANS; ISONIAZID; MICROBIAL SENSITIVITY TESTS; MYCOBACTERIUM; MYCOBACTERIUM BOVIS; MYCOBACTERIUM SMEGMATIS; MYCOBACTERIUM TUBERCULOSIS; OXIDOREDUCTASES; TRANSFORMATION, BACTERIAL;

ACTINOBACTERIA (CLASS); BACTERIA (MICROORGANISMS); CORYNEBACTERINEAE; MYCOBACTERIUM; MYCOBACTERIUM BOVIS BCG; MYCOBACTERIUM SMEGMATIS; MYCOBACTERIUM TUBERCULOSIS; PROKARYOTA; UNCULTURED ACTINOMYCETE;

EID: 18744398724     PISSN: 0950382X     EISSN: None     Source Type: Journal    
DOI: 10.1046/j.1365-2958.2002.03162.x     Document Type: Article

References (60)

1. Baca, A.M., Sirawaraporn, R., Turley, S., Sirawaraporn, W., and Hol, W.G. (2000) Crystal structure of Mycobacterium tuberculosis 7,8-dihydropteroate synthase in complex with pterin monophosphate: New insight into the enzymatic mechanism and sulfa-drug action. J Mol Biol 302: 1193-1212.
2. Banerjee, A., Dubnau, E., Quemard, A., Balasubramanian, V., Um, K.S., Wilson, T., et al. (1994) inhA, a gene encoding a target for isoniazid and ethionamide in Mycobacterium tuberculosis. Science 263:227-230.
3. Banerjee, A., Sugantino, M., Sacchettini, J.C., and Jacobs, W.R. (1998) The mabA gene from the inhA operon of Mycobacterium tuberculosis encodes a 3-ketoacyl reductase that fails to confer isoniazid resistance. Microbiology 144:2697-2704.
4. Barry, C.E., III (1997) New horizons in the treatment of tuberculosis. Biochem Pharmacol 54:1165-1172.
5. Barry, C.E. (2001) Mycobacterium smegmatis: An absurd model for tuberculosis? Trends Microbiol 9:473-474.
6. Basso, L.A., Zheng, R., Musser, J.M., Jacobs, W.R., and Blanchard, J.S. (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.
7. Baulard, A.R., Betts, J.C., Engohang-Ndong, J., Quan, S., McAdam, R.A., Brennan, P.J., et al. (2000) Activation of the pro-drug ethionamide is regulated in mycobacteria. J Biol Chem 275:28326-28331.
8. Bernstein, J.W., Lott, W.A., Steinberg, B.A., and Yale, H.L. (1952) Chemotherapy of experimental tuberculosis. Am Rev Tuberc 65:357-374.
9. Davies, R.W., and Gronenborn, A.M. (1982) Molecular cloning of the gene for dihydrofolate reductase from Lactobacillus casei. Gene 17:229-233.
10. DeBarber, A.E., Mdluli, K., Bosman, M., Bekker, L.G., and Barry, C.E., III (2000) Ethionamide activation and sensitivity in multidrug-resistant Mycobacterium tuberculosis. Proc Natl Acad Sci USA 97:9677-9682.
11. Dessen, A., Quemard, A., Blanchard, J.S., Jacobs, W.R., and Sacchettini, J.C. (1995) Crystal structure and function of the isoniazid target of Mycobacterium tuberculosis. Science 267:1638-1641.
12. Donnelly-Wu, M.K., Jacobs, W.R., Jr, and Hatfull, G.F. (1993) Superinfection immunity of mycobacteriophage L5: Applications for genetic transformation of mycobacteria. Mol Microbiol 7:407-417.
13. Dubnau, E., Fontan, P., Manganelli, R., Soares-Appel, S., and Smith, I. (2002) Mycobacterium tuberculosis genes induced during infection of human macrophages. Infect Immun 70:2787-2795.
14. Duncan, K., and Sacchettini, J.C. (2000) Approaches to tuberculosis drug development. In Molecular Genetics of Mycobacteria. Hatfull, G.F., and Jacobs, W.R. (eds). Washington, DC: American Society for Microbiology Press, pp. 297-312.
15. Fox, H.H. (1952) The chemical approach to the control of tuberculosis. Science 116:129-134.
16. Gold, B., Rodriquez, R., Marras, S., Pentecost, M., and Smith, I. (2001) The Mycobacterium tuberculosis IdeR is a dual functional regulator that controls transcription of genes involved in iron acquisition, iron storage, and survival in macrophages. Mol Microbiol 42:851-865.
17. Hampele, I.C., D'Arcy, A., Dale, G.E., Kostrewa, D., Nielsen, J., Oefner, C., et al. (1997) Structure and function of the dihydropteroate synthase from Staphylococcus aureus. J Mol Biol 268:21-30.
18. Heifets, L.B. (1991) Drug Susceptibility in the Chemotherapy of Mycobacterial Infections. Boston: CRC Press.
19. Heym, B., Honore, N., Truffot-Pernot, C., Banerjee, A., Schurra, C., Jacobs, W.R., et al. (1994) Implications of multidrug resistance for the future of short-course chemotherapy of tuberculosis: A molecular study. Lancet 344: 293-298.
20. Johnsson, K., and Schultz, P.G. (1994) Mechanistics studies of the oxidation of isoniazid by the catalase peroxidase from Mycobacterium tuberculosis. J Am Chem Soc 116:7425-7426.
21. Kiepiela, P., Bishop, K., Smith, A.N., Roux, L., and York, D.F. (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. Tubercle Lung Dis 80:47-56.
22. Kikuchi, S., Rainwater, D.L., and Kolattukudy, P.E. (1992) Purification and characterization of an unusually large fatty acid synthase from Mycobacterium tuberculosis var. bovis BCG. Arch Biochem Biophys 295:318-326.
23. Kremer, L., Douglas, J.D., Baulard, A.R., Morehouse, C., Guy, M.R., Alland, D., et al. (2000) Thiolactomycin and related analogues as novel anti-mycobacterial agents targeting KasA and KasB condensing enzymes in Mycobacterium tuberculosis. J Biol Chem 275:16857-16864.
24. Lee, A.S., Lim, I.H., Tang, L.L., Telenti, A., and Wong, S.Y. (1999) Contribution of kasA analysis to detection of isoniazid-resistant Mycobacterium tuberculosis. Singapore. Antimicrob Agents Chemother 43:2087-2089.
25. Lee, A.S., Teo, A.S., and Wong, S.Y. (2001) Novel mutations in ndh in isoniazid-resistant Mycobacterium tuberculosis isolates. Antimicrob Agents Chemother 45:2157-2159.
26. Leszczynska, K., Bolhuis, A., Leenhouts, K., Venema, G., and Ceglowski, P. (1995) Cloning and molecular analysis of the dihydrofolate reductase gene fromLactococcus lactis. Appl Environ Microbiol 61:561-566.
27. Li, R., Sirawaraporn, R., Chitnumsub, P., Sirawaraporn, W., Wooden, J., Athappilly, F.,et al. (2000) Three-dimensional structure of M. tuberculosis dihydrofolate reductase reveals opportunities for the design of novel tuberculosis drugs. J Mol Biol 295:307-323.
28. Manganelli, R., Dubnau, E., Tyagi, S., Kramer, F.R., and Smith, I. (1999) Differential expression of 10 sigma factor genes in Mycobacterium tuberculosis. Mol Microbiol 31:715-724.
29. Mdluli, K., Sherman, D.R., Hickey, M.J., Kreiswirth, B.N., Morris, S., Stover, C.K., and Barry, C.E. (1996) Biochemical and genetic data suggest that InhA is not the primary target for activated isoniazid in Mycobacterium tuberculosis. J Infect Dis 174:1085-1090.
30. Mdluli, K., Slayden, R.A., Zhu, Y., Ramaswamy, S., Pan, X., Mead, D.,et al. (1998) Inhibition of a Mycobacterium tuberculosis beta-ketoacyl ACP synthase by isoniazid. Science 280:1607-1610.
31. Nagate, T., Inoue, M., Inoue, K., and Mitsuhashi, S. (1978) Plasmid-mediated sulfanilamide resistance. Microbiol Immunol 22:367-375.
32. O'Brien, K.L., Dietz, H.C., Romagnoli, M., and Eiden, J. (1996) Evaluation of inhA gene and catalase-peroxidase gene among isoniazid-sensitive and resistant Mycobacterium tuberculosis isolates. Mol Cell Probes 10:1-6.
33. Peterson, D.O., and Bloch, K. (1977) Mycobacterium smegmatis fatty acid synthetase. Long chain transacylase chain length specificity. J Biol Chem 252:5735-5739.
34. Piatek, A.S., Telenti, A., Murray, M.R., El-Hajj, H., Jacobs, W.R., Jr, Kramer, F.R., and Alland, D. (2000) Genotypic analysis of Mycobacterium tuberculosis. Two distinct populations using molecular beacons: Implications for rapid susceptibility testing. Antimicrob Agents Chemother 44:103-110.
35. Quemard, A., Sacchettini, J.C., Dessen, A., Vilcheze, C., Bittman, R., Jacobs, W.R., and Blanchard, J.S. (1995) Enzymatic characterization of the target for isoniazid in Mycobacterium tuberculosis. Biochemistry 34: 8235-8241.
36. Quemard, A., Dessen, A., Sugantino, M., Jacobs, W.R., Sacchettini, J.C., and Blanchard, J.S. (1996) Binding of catalase-peroxidase activated isoniazid to wild-type and mutant Mycobacterium tuberculosis enoyl-ACP reductases. J Am Chem Soc 118:1561-1562.
37. Ristow, M., Mohlig, M., Rifai, M., Schatz, H., Feldmann, K., and Pfeiffer, A. (1995) New isoniazid/ethionamide resistance gene mutation and screening for multidrug-resistant Mycobacterium tuberculosis strains. Lancet 346: 502-503.
38. Rock, C.O., and Cronan, J.E. (1996) Escherichia coli as a model for the regulation of dissociable (type II) fatty acid biosynthesis. Biochim Biophys Acta 1302:1-16.
39. Rouse, D.A., Li, Z., Bai, G.H., and Morris, S.L. (1995) Characterization of the katG and inhA genes of isoniazid-resistant clinical isolates of Mycobacterium tuberculosis. Antimicrob Agents Chemother 39:2472-2477.
40. Rozwarski, D.A., Grant, G.A., Barton, D.H., Jacobs, W.R., and Sacchettini, J.C. (1998) Modification of the NADH of the isoniazid target (InhA) from Mycobacterium tuberculosis. Science 279:98-102.
41. Schimke, R.T., Kaufman, R.J., Alt, F.W., and Kellems, R.F. (1978) Gene amplification and drug resistance in cultured murine cells. Science 202:1051-1055.
42. Skold, O. (1976) R-factor-mediated resistance to sulfonamides by a plasmid-borne, drug-resistant dihydropteroate synthase. Antimicrob Agents Chemother 9:49-54.
43. Slayden, R.A., and Barry, C.E., III (2000) The genetics and biochemistry of isoniazid resistance in Mycobacterium tuberculosis. Microbes Infect 2:659-669.
44. Slayden, R.A., Lee, R.E., Armour, J.W., Cooper, A.M., Orme, I.M., Brennan, P.J., and Besra, G.S. (1996) Antimycobacterial action of thiolactomycin: An inhibitor of fatty acid and mycolic acid synthesis. Antimicrob Agents Chemother 40:2813-2819.
45. Slayden, R.A., Lee, R.E., and Barry, C.E. (2000) Isoniazid affects multiple components of the type II fatty acid synthase system of Mycobacterium tuberculosis. Mol Microbiol 38:514-525.
46. Smith, D.R., Rood, J.I., Bird, P.I., Sneddon, M.K., Calvo, J.M., and Morrison, J.F. (1982) Amplification and modification of dihydrofolate reductase in Escherichia coli. Nucleotide sequence of fol genes from mutationally altered plasmids. J Biol Chem 257:9043-9048.
47. Snapper, S.B., Lugosi, L., Jekkel, A., Melton, R.E., Kieser, T., Bloom, B.R., and Jacobs, W.R., Jr (1988) Lysogeny and transformation in mycobacteria: Stable expression of foreign genes. Proc Natl Acad Sci USA 85:6987-6991.
48. Snapper, S.B., Melton, R.E., Mustafa, S., Kieser, T., and Jacobs, W.R., Jr (1990) Isolation and characterization of efficient plasmid transformation mutants of Mycobacterium smegmatis. Mol Microbiol 4:1911-1919.
49. Stover, C.K., de la Cruz, V.F., Fuerst, T.R., Burlein, J.E., Benson, L.A., Bennett, L.T.,et al. (1991) New use of BCG for recombinant vaccines. Nature 351:456-460.
50. Swedberg, G., Castensson, S., and Skold, O. (1979) Characterization of mutationally altered dihydropteroate synthase and its ability to form a sulfonamide-containing dihydrofolate analog. J Bacteriol 137:129-136.
51. Takayama, K., Wang, L., and David, H.L. (1972) Effect of isoniazid on the in vivo mycolic acid synthesis, cell growth, and viability of Mycobacterium tuberculosis. Antimicrob Agents Chemother 2:29-35.
52. Takayama, K., Schnoes, H.K., Armstrong, E.L., and Boyle, R.W. (1975) Site of inhibitory action of isoniazid in the synthesis of mycolic acids in Mycobacterium tuberculosis. J Lipid Res 16:308-317.
53. Telenti, A., Honore, N., Bernasconi, C., March, J., Ortega, A., Heym, B.,et al. (1997) Genotypic assessment of isoniazid and rifampin resistance in Mycobacterium tuberculosis: A blind study at reference laboratory level. J Clin Microbiol 35:719-723.
54. Vilcheze, C., Morbidoni, H.R., Weisbrod, T.R., Iwamoto, H., Kuo, M., Sacchettini, J.C., and Jacobs, W.R. (2000) Inactivation of the inhA-encoded fatty acid synthase II (FASII) enoylacyl carrier protein reductase induces accumulation of the FASI end products and cell lysis of Mycobacterium smegmatis. J Bacteriol 182:4059-4067.
55. Wilson, T.M., de Lisle, G.W., and Collins, D.M. (1995) Effect of inhA and katG on isoniazid resistance and virulence of Mycobacterium bovis. Mol Microbiol 15: 1009-1015.
56. Wilson, M., DeRisi, J., Kristensen, H.H., Imboden, P., Rane, S., Brown, P.O., and Schoolnik, G.K. (1999) Exploring drug-induced alterations in gene expression in Mycobacterium tuberculosis by microarray hybridization. Proc Natl Acad Sci USA 96:12833-12838.
57. Winder, F.G., and Collins, P.B. (1970) Inhibition by isoniazid of synthesis of mycolic acids in Mycobacterium tuberculosis. J Gen Microbiol 63:41-48.
58. Wise, E.M., Jr, and Abou-Donia, M.M. (1975) Sulfonamide resistance mechanism in Escherichia coli: R plasmids can determine sulfonamide-resistant dihydropteroate synthases. Proc Natl Acad Sci USA 72:2621-2625.
59. Zhang, Y., Heym, B., Allen, B., Young, D., and Cole, S. (1992) The catalase-peroxidase gene and isoniazid resistance of Mycobacterium tuberculosis. Nature 358: 591-593.
60. Zhang, Y., Garbe, T., and 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.