1887

Microbiology Society logo

Volume 151, Issue 6

Altered expression profile of mycobacterial surface glycopeptidolipids following treatment with the antifungal azole inhibitors econazole and clotrimazole Free

Abstract

The azole antifungal drugs econazole and clotrimazole are known cytochrome P450 enzyme inhibitors. This study shows that these drugs are potent inhibitors of mycobacterial growth and are more effective against than isoniazid and ethionamide, two established anti-mycobacterial drugs. Several non-tuberculous mycobacteria, including the pathogenic members of the – complex (MAC) and the fast-growing saprophytic organism , produce an array of serovar-specific (ss) and non-serovar-specific (ns) glycopeptidolipids (GPLs). GPL biosynthesis has been investigated for several years but has still not been fully elucidated. The authors demonstrate here that econazole and clotrimazole inhibit GPL biosynthesis in . In particular, clotrimazole inhibits all four types of nsGPLs found in , suggesting an early and common target within their biosynthetic pathway. Altogether, the data suggest that an azole-specific target, most likely a cytochrome P450, may be involved in the hydroxylation of the -acyl chain in GPL biosynthesis. Azole antifungal drugs and potential derivatives could represent an interesting new range of anti-mycobacterial drugs, especially against opportunistic human pathogens including MAC, , , and .

  • Received:
  • Accepted:
  • Published Online:
Keyword(s): 6-dTal, 6-deoxytalose , CAD-ES-MS/MS, collision-activated dissociation electrospray mass spectrometry–mass spectrometry , dGPL, de-O-acylated GPL , EMB, ethambutol , ETH, ethionamide , GPL, glycopeptidolipid , INH, isoniazid , LOS, lipooligosaccharide , MAC, Mycobacterium avium–intracellulare complex , nsGPL, non-serovar-specific-GPL , PGL, phenolic glycolipid , Rha, rhamnose and ssGPL, serovar-specific-GPL
SGM
Loading

Article metrics loading...

/content/journal/micro/10.1099/mic.0.27938-0
2005-06-01
2024-04-25
Loading full text...

Full text loading...

/deliver/fulltext/micro/151/6/mic1512087.html?itemId=/content/journal/micro/10.1099/mic.0.27938-0&mimeType=html&fmt=ahah

References

  1. Aspinall G. O., Chatterjee D., Brennan P. J. 1995; The variable surface glycolipids of mycobacteria: structures, synthesis of epitopes, and biological properties. Adv Carbohydr Chem Biochem 51:169–242
     [Google Scholar]
  2. Banerjee A., Dubnau E., Quemard A. 7 other authors 1994; inhA, a gene encoding a target for isoniazid and ethionamide in Mycobacterium tuberculosis. Science 263:227–230 [CrossRef]
     [Google Scholar]
  3. Belisle J. T., Brennan P. J. 1989; Chemical basis of rough and smooth variation in mycobacteria. J Bacteriol 171:3465–3470
     [Google Scholar]
  4. Belisle J. T., Pascopella L., Inamine J. M., Brennan P. J., Jacobs W. R. Jr 1991; Isolation and expression of a gene cluster responsible for biosynthesis of the glycopeptidolipid antigens of Mycobacterium avium . J Bacteriol 173:6991–6997
     [Google Scholar]
  5. Belisle J. T., Klaczkiewicz K., Brennan P. J., Jacobs W. R., Inamine J. M. Jr 1993a; Rough morphological variants of Mycobacterium avium. Characterization of genomic deletions resulting in the loss of glycopeptidolipid expression. J Biol Chem 268:10517–10523
     [Google Scholar]
  6. Belisle J. T., McNeil M. R., Chatterjee D., Inamine J. M., Brennan P. J. 1993b; Expression of the core lipopeptide of the glycopeptidolipid surface antigens in rough mutants of Mycobacterium avium . J Biol Chem 268:10510–10516
     [Google Scholar]
  7. Bellamine A., Mangla A. T., Nes W. D., Waterman M. R. 1999; Characterization and catalytic properties of the sterol 14alpha-demethylase from Mycobacterium tuberculosis . Proc Natl Acad Sci U S A 96:8937–8942 [CrossRef]
     [Google Scholar]
  8. Besra G. S., McNeil M. R., Khoo K. H., Dell A., Morris H. R., Brennan P. J. 1993a; Trehalose-containing lipooligosaccharides of Mycobacterium gordonae: presence of a mono-O-methyltetra-O-acyltrehalose “core” and branching in the oligosaccharide backbone. Biochemistry 32:12705–12714 [CrossRef]
     [Google Scholar]
  9. Besra G. S., McNeil M. R., Rivoire B., Khoo K. H., Morris H. R., Dell A., Brennan P. J. 1993b; Further structural definition of a new family of glycopeptidolipids from Mycobacterium xenopi . Biochemistry 32:347–355 [CrossRef]
     [Google Scholar]
  10. Besra G. S., Gurcha S. S., Khoo K. H., Morris H. R., Dell A., Hamid M. E., Minnikin D. E., Goodfellow M., Brennan P. J. 1994; Characterization of the specific antigenicity of representatives of M. senegalense and related bacteria. Zentralbl Bakteriol 281:415–432 [CrossRef]
     [Google Scholar]
  11. Billman-Jacobe H., McConville M. J., Haites R. E., Kovacevic S., Coppel R. L. 1999; Identification of a peptide synthetase involved in the biosynthesis of glycopeptidolipids of Mycobacterium smegmatis. Mol Microbiol 33:1244–1253
     [Google Scholar]
  12. Brennan P. J. 1988 In Microbial Lipids pp 203–298 Edited by Ratledge C., Wilkinson S. G. London: Academic Press;
     [Google Scholar]
  13. Brennan P. J., Goren M. B. 1979; Structural studies on the type-specific antigens and lipids of the Mycobacterium avium,Mycobacterium intracellulare, Mycobacterium scrofulaceum serocomplex. Mycobacterium intracellulare serotype 9. J Biol Chem 254:4205–4211
     [Google Scholar]
  14. Brennan P. J., Nikaido H. 1995; The envelope of mycobacteria. Annu Rev Biochem 64:29–63 [CrossRef]
     [Google Scholar]
  15. Camphausen R. T., Jones R. L., Brennan P. J. 1988; Antigenic relationship between Mycobacterium paratuberculosis and Mycobacterium avium . Am J Vet Res 49:1307–1310
     [Google Scholar]
  16. Chatterjee D., Bozic C. M., Knisley C., Cho S. N., Brennan P. J. 1989; Phenolic glycolipids of Mycobacterium bovis: new structures and synthesis of a corresponding seroreactive neoglycoprotein. Infect Immun 57:322–330
     [Google Scholar]
  17. Cole S. T., Brosch R., Parkhill J. & 39 other authors; 1998; Deciphering the biology of Mycobacterium tuberculosis from the complete genome sequence. Nature 393:537–544 [CrossRef]
     [Google Scholar]
  18. Daffé M. 1989; Further specific triglycosyl phenol phthiocerol diester from Mycobacterium tuberculosis. Biochim Biophys Acta 1002:257–260 [CrossRef]
     [Google Scholar]
  19. Daffé M., Lanéelle M. A., Puzo G. 1983; Structural elucidation by field desorption and electron-impact mass spectrometry of the C-mycosides isolated from Mycobacterium smegmatis . Biochim Biophys Acta 751:439–443 [CrossRef]
     [Google Scholar]
  20. Daffé M., Lacave C., Lanéelle M. A., Lanéelle G. 1987; Structure of the major triglycosyl phenol-phthiocerol of Mycobacterium tuberculosis (strain Canetti. Eur J Biochem 167:155–160 [CrossRef]
     [Google Scholar]
  21. Daffé M., McNeil M., Brennan P. J. 1991; Novel type-specific lipooligosaccharides from Mycobacterium tuberculosis. Biochemistry 30:378–388 [CrossRef]
     [Google Scholar]
  22. Dell A., Khoo K.-H., Panico M., McDowell R. A., Etienne A. T., Reason A. J., Morris H. R. 1993 In Glycobiology: a Practical Approach pp 187–222 Edited by Fukuda M., Kobata A. Oxford: Oxford University Press;
     [Google Scholar]
  23. Dell A., Reason A. J., Khoo K.-H., Panico M., McDowell R. A., Morris H. R. 1994; Mass spectrometry of carbohydrate-containing biopolymers. Methods Enzymol 230:108–132
     [Google Scholar]
  24. Dobson G., Minnikin D. E., Minnikin S. M., Parlett M., Goodfellow M., Ridell M., Magnusson M. 1985; Systematic analysis of complex mycobacterial lipids. In Chemical Methods in Bacterial Systematics pp 237–265 Edited by Goodfellow M., Minnikin D. E. London: Academic Press;
     [Google Scholar]
  25. Dobson G., Minnikin D. E., Besra G. S., Mallet A. I., Magnusson M. 1990; Characterisation of phenolic glycolipids from Mycobacterium marinum. Biochim Biophys Acta 1042:176–181 [CrossRef]
     [Google Scholar]
  26. Eckstein T. M., Belisle J. T., Inamine J. M. 2003; Proposed pathway for the biosynthesis of serovar-specific glycopeptidolipids in Mycobacterium avium serovar 2. Microbiology 149:2797–2807 [CrossRef]
     [Google Scholar]
  27. Fournie J. J., Riviere M., Puzo G. 1987; Structural elucidation of the major phenolic glycolipid from Mycobacterium kansasii. I. Evidence for tetrasaccharide structure of the oligosaccharide moiety. J Biol Chem 262:3174–3179
     [Google Scholar]
  28. Gilleron M., Vercauteren J., Puzo G. 1993; Lipooligosaccharidic antigen containing a novel C4-branched 3,6-dideoxy-alpha-hexopyranose typifies Mycobacterium gastri . J Biol Chem 268:3168–3179
     [Google Scholar]
  29. Guardiola-Diaz H. M., Foster L. A., Mushrush D., Vaz A. D. 2001; Azole-antifungal binding to a novel cytochrome P450 from Mycobacterium tuberculosis: implications for treatment of tuberculosis. Biochem Pharmacol 61:1463–1470 [CrossRef]
     [Google Scholar]
  30. Guengerich F. P. 2001; Common and uncommon cytochrome P450 reactions related to metabolism and chemical toxicity. Chem Res Toxicol 14:611–650 [CrossRef]
     [Google Scholar]
  31. Hitchcock C. A., Dickinson K., Brown S. B., Evans E. G., Adams D. J. 1990; Interaction of azole antifungal antibiotics with cytochrome P-450-dependent 14 alpha-sterol demethylase purified from Candida albicans . Biochem J 266:475–480
     [Google Scholar]
  32. Hunter S. W., Fujiwara T., Brennan P. J. 1982; Structure and antigenicity of the major specific glycolipid antigen of Mycobacterium leprae . J Biol Chem 257:15072–15078
     [Google Scholar]
  33. Imai T., Globerman H., Gertner J. M., Kagawa N., Waterman M. R. 1993; Expression and purification of functional human 17 alpha-hydroxylase/17,20-lyase (P450c17) in Escherichia coli. Use of this system for study of a novel form of combined 17 alpha-hydroxylase/17,20-lyase deficiency. J Biol Chem 268:19681–19689
     [Google Scholar]
  34. Jackson C. J., Lamb D. C., Marczylo T. H., Parker J. E., Manning N. L., Kelly D. E., Kelly S. L. 2003; Conservation and cloning of CYP51: a sterol 14 alpha-demethylase from Mycobacterium smegmatis . Biochem Biophys Res Commun 301:558–563 [CrossRef]
     [Google Scholar]
  35. Jeevarajah D., Patterson J. H., McConville M. J., Billman-Jacobe H. 2002; Modification of glycopeptidolipids by an O-methyltransferase of Mycobacterium smegmatis . Microbiology 148:3079–3087
     [Google Scholar]
  36. Jeevarajah D., Patterson J. H., Taig E., Sargeant T., McConville M. J., Billman-Jacobe H. 2004; Methylation of GPLs in Mycobacterium smegmatis and Mycobacterium avium . J Bacteriol 186:6792–6799 [CrossRef]
     [Google Scholar]
  37. Ji H., Zhang W., Zhou Y., Zhang M., Zhu J., Song Y., Lu J. 2000; A three-dimensional model of lanosterol 14alpha-demethylase of Candida albicans and its interaction with azole antifungals. J Med Chem 43:2493–2505 [CrossRef]
     [Google Scholar]
  38. Kamisango K., Saadat S., Dell A., Ballou C. E. 1985; Pyruvylated glycolipids from Mycobacterium smegmatis. Nature and location of the lipid components. J Biol Chem 260:4117–4121
     [Google Scholar]
  39. Karakousis P. C., Bishai W. R., Dorman S. E. 2004; Mycobacterium tuberculosis cell envelope lipids and the host immune response. Cell Microbiol 6:105–116 [CrossRef]
     [Google Scholar]
  40. Khoo K. H., Suzuki R., Morris H. R., Dell A., Brennan P. J., Besra G. S. 1995; Structural definition of the glycopeptidolipids and the pyruvylated, glycosylated acyltrehalose from Mycobacterium butyricum . Carbohydr Res 276:449–455 [CrossRef]
     [Google Scholar]
  41. Khoo K. H., Chatterjee D., Dell A., Morris H. R., Brennan P. J., Draper P. 1996a; Novel O-methylated terminal glucuronic acid characterizes the polar glycopeptidolipids of Mycobacterium habana strain TMC 5135. J Biol Chem 271:12333–12342 [CrossRef]
     [Google Scholar]
  42. Khoo K. H., Douglas E., Azadi P., Inamine J. M., Besra G. S., Mikusova K., Brennan P. J., Chatterjee D. 1996b; Truncated structural variants of lipoarabinomannan in ethambutol drug-resistant strains of Mycobacterium smegmatis. Inhibition of arabinan biosynthesis by ethambutol. J Biol Chem 271:28682–28690 [CrossRef]
     [Google Scholar]
  43. Khoo K. H., Jarboe E., Barker A., Torrelles J., Kuo C. W., Chatterjee D. 1999; Altered expression profile of the surface glycopeptidolipids in drug-resistant clinical isolates of Mycobacterium avium complex. J Biol Chem 274:9778–9785 [CrossRef]
     [Google Scholar]
  44. Kremer L., Douglas J. D., Baulard A. R. 9 other authors 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 [CrossRef]
     [Google Scholar]
  45. Krzywinska E., Krzywinski J., Schorey J. S. 2004; Phylogeny of Mycobacterium avium strains inferred from glycopeptidolipid biosynthesis pathway genes. Microbiology 150:1699–1706 [CrossRef]
     [Google Scholar]
  46. Lamb D., Kelly D., Kelly S. 1999; Molecular aspects of azole antifungal action and resistance. Drug Resist Updat 2:390–402 [CrossRef]
     [Google Scholar]
  47. Lewis D. F. V. 1996 In Cytochromes P450: Structure, Function and Mechanism London: Taylor & Francis;
     [Google Scholar]
  48. McLean K. J., Cheesman M. R., Rivers S. L. 9 other authors 2002a; Expression, purification and spectroscopic characterization of the cytochrome P450 CYP121 from Mycobacterium tuberculosis . J Inorg Biochem 91:527–541 [CrossRef]
     [Google Scholar]
  49. McLean K. J., Marshall K. R., Richmond A., Hunter I. S., Fowler K., Kieser T., Gurcha S. S., Besra G. S., Munro A. W. 2002b; Azole antifungals are potent inhibitors of cytochrome P450 mono-oxygenases and bacterial growth in mycobacteria and streptomycetes. Microbiology 148:2937–2949
     [Google Scholar]
  50. McNeil M., Tsang A. Y., Brennan P. J. 1987; Structure and antigenicity of the specific oligosaccharide hapten from the glycopeptidolipid antigen of Mycobacterium avium serotype 4, the dominant Mycobacterium isolated from patients with acquired immune deficiency syndrome. J Biol Chem 262:2630–2635
     [Google Scholar]
  51. Mederos L. M., Valdivia J. A., Sempere M. A., Valero-Guillen P. L. 1998; Analysis of lipids reveals differences between ‘Mycobacterium habana’ and Mycobacterium simiae. Microbiology 144:1181–1188 [CrossRef]
     [Google Scholar]
  52. Minnikin D. E. 1982 In the Biology of the Mycobacteria pp 95–104 Edited by Ratledge C., Stanford J. L. London: Academic Press;
     [Google Scholar]
  53. Navalkar R. G., Wiegeshaus E., Kondo E., Kim K., Smith D. W. 1965; Mycoside G, a specific glycolipid in Mycobacterium marinum (Balnei). J Bacteriol 90:262–265
     [Google Scholar]
  54. Nelson D. R., Kamataki T., Waxman D. J. & 9 other authors; 1993; The P450 superfamily: update on new sequences, gene mapping, accession numbers, early trivial names of enzymes, and nomenclature. DNA Cell Biol 12:1–51 [CrossRef]
     [Google Scholar]
  55. Nes W. R. 1974; Role of sterols in membranes. Lipids 9:596–612 [CrossRef]
     [Google Scholar]
  56. Nishiuchi Y., Kitada S., Maekura R. 2004; Liquid chromatography/mass spectrometry analysis of small-scale glycopeptidolipid preparations to identify serovars of Mycobacterium avium–intracellulare complex. J Appl Microbiol 97:738–748 [CrossRef]
     [Google Scholar]
  57. Patterson J. H., McConville M. J., Haites R. E., Coppel R. L., Billman-Jacobe H. 2000; Identification of a methyltransferase from Mycobacterium smegmatis involved in glycopeptidolipid synthesis. J Biol Chem 275:24900–24906 [CrossRef]
     [Google Scholar]
  58. Riviere M., Puzo G. 1991; A new type of serine-containing glycopeptidolipid from Mycobacterium xenopi . J Biol Chem 266:9057–9063
     [Google Scholar]
  59. Riviere M., Fournie J. J., Puzo G. 1987; A novel mannose containing phenolic glycolipid from Mycobacterium kansasii . J Biol Chem 262:14879–14884
     [Google Scholar]
  60. Sarda P., Gastambide-Odier M. 1967; Structure chimique de l'aglycone du mycoside G de Mycobacterium marinum. Chem Phys Lipids 1:434–444 [CrossRef]
     [Google Scholar]
  61. Vergne I., Daffé M. 1998; Interaction of mycobacterial glycolipids with host cells. Front Biosci 3:d865–d876
     [Google Scholar]
  62. Vergne I., Desbat B. 2000; Influence of the glycopeptidic moiety of mycobacterial glycopeptidolipids on their lateral organization in phospholipid monolayers. Biochim Biophys Acta 1467113–123 [CrossRef]
     [Google Scholar]
http://instance.metastore.ingenta.com/content/journal/micro/10.1099/mic.0.27938-0
Loading
Altered expression profile of mycobacterial surface glycopeptidolipids following treatment with the antifungal azole inhibitors econazole and clotrimazole
Microbiology 151, 2087 (2005); https://doi.org/10.1099/mic.0.27938-0
/content/journal/micro/10.1099/mic.0.27938-0
/content/journal/micro/10.1099/mic.0.27938-0
Loading

Data & Media loading...

Most cited Most Cited RSS feed

This is a required field
Please enter a valid email address
Approval was a Success
Invalid data
An Error Occurred
Approval was partially successful, following selected items could not be processed due to error