Chapter 32 : Strategies for New Drug Development

MyBook is a cheap paperback edition of the original book and will be sold at uniform, low price.

Preview this chapter:
Zoom in

Strategies for New Drug Development, Page 1 of 2

| /docserver/preview/fulltext/10.1128/9781555818357/9781555819101_Chap32-1.gif /docserver/preview/fulltext/10.1128/9781555818357/9781555819101_Chap32-2.gif


This chapter focuses on the prospects for using a fundamental molecular approach to identification of novel lead compounds for new drug development. A section reviews existing and potential drug targets in . The chapter then discusses distinctive features of mycobacteria relevant to drug design, and considers experimental approaches applicable to rational drug discovery programs. Most antibacterial agents inhibit biosynthetic pathways involved in the production of macromolecules. Streptomycin, the first antibiotic available for widespread use in treatment of tuberculosis, is a member of the aminoglycoside family that disrupts bacterial protein synthesis. An important strategy for enhancing the activity of sulfonamides against some bacteria has been their use in combination with trimethoprim, a drug that inhibits a subsequent step in the tetrahydrofolate pathway catalyzed by the enzyme dihydrofolate reductase. Rifampin is a key drug in mycobacterial therapy that has a broad antibacterial spectrum and a well-defined target. Ethambutol has a polyamine-like structure and was originally thought to interfere with RNA synthesis. isolates with defects in the gene encoding a catalase-peroxidase enzyme develop resistance to isoniazid (INH), indicating a possible role for the enzyme in intracellular activation of the drug. The recent development of molecular genetic systems for mycobacteria opens a range of novel opportunities for drug discovery.

Citation: Young D. 1994. Strategies for New Drug Development, p 559-567. In Bloom B (ed), Tuberculosis. ASM Press, Washington, DC. doi: 10.1128/9781555818357.ch32
Highlighted Text: Show | Hide
Loading full text...

Full text loading...


Image of Figure 1.
Figure 1.

Sites of action of antimycobacterial agents. PABA, -aminobenzoic acid; DHFR, dihydrofolate reductase; PAS, -aminosalicylic acid.

Citation: Young D. 1994. Strategies for New Drug Development, p 559-567. In Bloom B (ed), Tuberculosis. ASM Press, Washington, DC. doi: 10.1128/9781555818357.ch32
Permissions and Reprints Request Permissions
Download as Powerpoint
Image of Figure 2.
Figure 2.

Structures of Antimycobacterial agents.

Citation: Young D. 1994. Strategies for New Drug Development, p 559-567. In Bloom B (ed), Tuberculosis. ASM Press, Washington, DC. doi: 10.1128/9781555818357.ch32
Permissions and Reprints Request Permissions
Download as Powerpoint


1. Abou-Zeid, C.,, T. Garbe,, R. Lathigra,, H. G. Wiker,, M. Harboe,, G. A. W. Rook,, and D. B. Young. 1991. Genetic and immunological analysis of Mycobacterium tuberculosis fibronectin-binding proteins. Infect. Immun. 59: 2712 2718.
2. Andersen, A. B.,, L. Ljungqvist,, and M. Olsen. 1990. Evidence that protein antigen b of Mycobacterium tuberculosis is involved in phosphate metabolism. J. Gen. Microbiol. 136: 477 480.
3. Bannerjee, A.,, and W. R. Jacobs. Personal communication.
4. Beaman, L.,, and B. L. Beaman. 1990. Monoclonal antibodies demonstrate that superoxide dismutase contributes to protection of Nocardia asteroides within the intact host. Infect. Immun. 58: 3122 3128.
5. Chatterjee, D.,, A. D. Roberts,, K. Lowell,, P. J. Brennan,, and I. M. Orme. 1992. Structural basis of capacity of lipoarabinomannan to induce secretion of tumor necrosis factor. Infect. Immun. 60: 1249 1253.
6. Cooper, J. B.,, H. P. C. Driessen,, S. P. Wood,, Y. Zhang,, and D. Young. Crystallization and preliminary X-ray analysis of the superoxide dismutase from Mycobacterium tuberculosis. J. Mol. Biol., in press.
7. Crowle, A. J.,, R. Dahl,, E. Ross,, and M. H. May. 1991. Evidence that vesicles containing living virulent Mycobacterium tuberculosis or Mycobacterium avium in cultured human macrophages are not acidic. Infect. Immun. 59: 1823 1831.
8. Daffe, M.,, P. J. Brennan,, and M. McNeil. 1990. Predominant structural features of the cell wall arabinogalactan of Mycobacterium tuberculosis as revealed through characterization of oligoglycosyl alditol fragments by gas chromatography/mass spectrometry and by 1H and 13C NMR analyses. J. Biol. Chem. 265: 6734 6743.
9. Fifis, T.,, C. Costopoulos,, A. J. Radford,, A. Back,, and P. R. Wood. 1991. Purification and characterization of major antigens from a Mycobacterium bovis culture filtrate. Infect. Immun. 59: 800 807.
10. Finken, M.,, P. Kirschner,, A. Meier,, A. Wrede,, and E. C. Bottger. 1993. Molecular basis of streptomycin resistance in Mycobacterium tuberculosis: alteration of the ribosomal protein S12 gene and point mutation within a functional 16S ribosomal RNA pseudoknot. Mol. Microbiol. 9: 1239 1246.
11. Garbe, T.,, D. Harris,, M. Vordermeier,, R. Lathigra,, J. Ivanyi,, and D. Young. 1993. Expression of the Mycobacterium tuberculosis 19-kilodalton antigen in Mycobacterium smegmatis: immunological analysis and evidence of glycosylation. Infect. Immun. 61: 260 267.
12. Hengge-Aronis, R. 1993. Survival of hunger and stress: the role of rpoS in early stationary phase gene regulation in E. coli. Cell 72: 165 168.
13. Hoffner, S. E.,, S. B. Svenson,, and G. KaUenius. 1987. Synergistic effects of antimycobacterial drug combinations on Mycobacterium avium complex determined radiometrically in liquid medium. Eur. J. Clin. Microbiol. 6: 530 535.
14. Inamine, J. Personal communication.
15. Jacobs, W. R.,, R. G. Barletta,, R. Udani,, J. Chan,, G. Kalkut,, G. Sosne,, T. Kieser,, G. J. Sarkis,, G. F. Hatfull,, and B. R. Bloom. 1993. Rapid assessment of drug susceptibilities of Mycobacterium tuberculosis by means of luciferase reporter phages. Science 260: 819 822.
16. Jarlier, V.,, L. Gutmann,, and H. Nikaido. 1991. Interplay of cell wall barrier and -lactamase activity determines high resistance to -lactam antibiotics in Mycobacterium chelonei. Antimicrob. Agents Chemother. 35: 1937 1939.
17. Jarlier, V.,, and H. Nikaido. 1990. Permeability barrier to hydrophilic solutes in Mycobacterium chelonei. J. Bacteriol. 172: 1418 1422.
18. Konno, K.,, F. M. Feldmann,, and W. McDermott. 1967. Pyrazinamide susceptibility and amidase activity of tubercle bacilli. Am. Rev. Respir. Dis. 95: 461 469.
19. Mackaness, G. B. 1956. The intracellular activation of pyrazinamide and nicotinamide. Am. Rev. Tuberc. 74: 718 728.
20. Matin, A.,, E. A. Auger,, P. H. Blum,, and J. E. Schultz. 1989. Genetic basis of survival in nondifferentiating bacteria. Annu. Rev. Microbiol. 43: 293 316.
21. Miller, J. F.,, J. J. Mekalanos,, and S. Falkow. 1989. Coordinate regulation and sensory transduction in the control of bacterial virulence. Science 243: 916 922.
22. Rastogi, N.,, K. S. Goh,, and H. L. David. 1990. Enhancement of drug susceptibility of Mycobacterium avium by inhibitors of cell envelope synthesis. Antimicrob. Agents Chemother. 34: 759 764.
23. Ratledge, C., 1982. Nutrition, growth and metabolism, p. 185 271. In C. Ratledge, and J. Stanford (ed.), The Biology of the Mycobacteria, vol. 1. Academic Press, London.
24. Siegele, D. A.,, and R. Kolter. 1992. Life after log. J. Bacteriol. 174: 345 348.
25. Takayama, K.,, and J. O. Kilburn. 1989. Inhibition of synthesis of arabinogalactan by ethambutol in Mycobacterium smegmatis. Antimicrob. Agents Chemother. 33: 1493 1499.
26. Takiff, H. Personal communication.
27. Telenti, A.,, P. Imboden,, F. Marchesi,, D. Lowrie,, S. Cole,, M. J. Colston,, L. Matter,, K. Schopfer,, and T. Bodmer. 1993. Detection of rifampicin-resistance mutations in Mycobacterium tuberculosis. Lancet 341: 647 650.
28. Trias, J.,, V. Jarlier,, and R. Benz. 1992. Porins in the cell wall of mycobacteria. Science 258: 1479 1481.
29. Winder, F. G., 1982. Mode of action of the antimycobacterial agents and associated aspects of the molecular biology of the mycobacteria, p. 353 438. In. C. Ratledge, and J. Stanford (ed.), The Biology of the Mycobacteria, vol. 1. Academic Press, London.
30. Winder, F. G.,, and P. B. Collins. 1970. Inhibition by isoniazid of synthesis of mycolic acids in Mycobacterium tuberculosis. J. Gen. Microbiol. 63: 41 48.
31. Young, D.,, T. Garbe,, R. Lathigra,, and C. Abou-Zeid,. 1990. Protein antigens: structure, function and regulation, p. 1 35. In J. McFadden (ed.), Molecular Biology of the Mycobacteria. Surrey University Press, London.
32. Young, D. B.,, and T. R. Garbe. 1991. Lipoprotein antigens of Mycobacterium tuberculosis. Res. Microbiol. 142: 55 65.
33. Zambrano, M. M.,, D. A. Siegele,, M. Almiron,, A. Tormo,, and R. Kolter. 1993. Microbial competition: Escherichia coli mutants that take over stationary phase cultures. Science 259: 1757 1760.
34. Zhang, Y.,, B. Heym,, B. Allen,, D. Young,, and S. Cole. 1992. The catalase-peroxidase gene and isoniazid resistance of Mycobacterium tuberculosis. Nature (London) 358: 591 593.
35. Zhang, Y.,, R. Lathigra,, T. Garbe,, D. Catty,, and D. Young. 1991. Genetic analysis of superoxide dismutase, the 23 kilodalton antigen of Mycobacterium tuberculosis. Mol. Microbiol. 5: 381 391.
36. Zhang, Y.,, and D. B. Young. 1993. Molecular mechanisms of isoniazid: a drug at the front line of tuberculosis control. Trends Microbiol. 1: 109 113.

This is a required field
Please enter a valid email address
Please check the format of the address you have entered.
Approval was a Success
Invalid data
An Error Occurred
Approval was partially successful, following selected items could not be processed due to error